Combinations of MENIN inhibitors and CYP3A4 inhibitors and methods of use thereof

Abstract

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

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180040679.5 (PCT / US2021 / 026141), with a filing date of April 7, 2021, and an invention title of "Combinations of MENIN Inhibitors and CYP3A4 Inhibitors and Methods of Use Thereof".

[0002] Cross - reference to related applications

[0003] This application claims the priority and benefit of U.S. Provisional Application No. 63 / 006,574, filed on April 7, 2020, the content of which is incorporated herein by reference in its entirety. Field of the invention

[0004] The present invention relates to inhibitors of the interaction of menin 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 the menin - MLL interaction. Background of the invention

[0006] The mixed - lineage leukemia (MLL) protein is a histone methyltransferase that is mutated in subsets of the clinical and biological features of acute leukemia. Rearranged mixed - lineage leukemia (MLL - r) involves recurrent translocations at the chromosomal locus 11q23, leading to aggressive forms of acute leukemia with limited treatment options. These translocations target the MLL gene, generating oncogenic fusion proteins that contain the amino - terminus of MLL fused in - frame with over 60 different fusion - protein partners. Menin is a widely expressed nuclear protein encoded by the multiple endocrine neoplasia type 1 (MEN1) tumor - suppressor gene, has a high - affinity binding interaction with MLL fusion proteins, and is an important co - factor for oncogenic MLL - r fusion proteins (Yokoyama et al., 2005, Cell, 123:207 - 18; Cierpicki & Grembecka, 2014, Future Med. Chem., 6:447 - 462). Disruption of this interaction results in 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).

[0007] The Menin-MLL complex plays a role in castration-resistant / advanced prostate cancer, and menin-MLL inhibitors have been shown to reduce tumor growth in vivo (Malik et al., 2015, Nat. Med., 21:344-352). In addition, menin-MLL inhibitors have been shown to enhance human β-cell proliferation (Chamberlain et al., 2014, J. Clin. Invest., 124:4093-4101), supporting the role of inhibitors of the menin-MLL interaction 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 novel combination therapies that inhibit the menin-MLL interaction are needed for the treatment of various diseases and conditions, including leukemia, other cancers, and diabetes. Summary of the Invention

[0009] The present invention provides a combination therapy that includes 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.

[0010] Some embodiments of the present invention relate to combination therapies designed to treat or manage cancer in a subject, wherein the combination therapy comprises administering a menin inhibitor in combination with a CYP3A inhibitor. In particular, some embodiments of the present invention 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 CYP3A inhibitor simultaneously, separately, or sequentially.

[0011] In some embodiments, the present invention provides a combination therapy that includes 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.

[0012] Some embodiments of the present invention relate to combination therapies designed for treating or managing cancer in a subject, wherein the combination therapy comprises administering a menin inhibitor in combination with a CYP3A4 inhibitor. In particular, some embodiments of the present invention 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.

[0013] In some embodiments, the CYP3A inhibitor is: an antiarrhythmic agent; 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 CYP3A inhibitor is: posaconazole, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobicistat (GS-9350); an analogue or derivative of cobicistat (GS-9350); cyclosporine; delavirdine; diazepam → 3-OH; diethyldithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; imatinib; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof.

[0014] In some embodiments, the CYP3A4 inhibitor is posaconazole, cobicistat (GS-9350), or an analogue 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 menin inhibitor and the CYP3A4 inhibitor are in separate dosage forms. In some embodiments, the pharmaceutical composition is in a combined dosage form. In some embodiments, the CYP3A4 inhibitor is posaconazole.

[0015] In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the oral bioavailability of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the C max of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the C max of the menin inhibitor to the C maxfrom about 20X to about 40X, or from about 25X to about 35X. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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.

[0016] In some embodiments, the pharmaceutical composition further comprises clopidymine, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibrutinib, 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.

[0017] In certain embodiments, a pharmaceutical combination is disclosed herein, comprising a therapeutically effective amount of a menin inhibitor and a CYP3A4 inhibitor. In some embodiments, the combination is in a combined dosage form. In some embodiments, the combination is in separate dosage forms. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered in parallel. 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; cobicistat (GS-9350); an analogue or derivative of cobicistat (GS-9350); cyclosporine; delavirdine; diazepam → 3-OH; diethyldithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; imatinib; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; star fruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; verapamil; troleandromycin; vincristine; voriconazole; or any combination thereof.

[0018] In some embodiments, the CYP3A4 inhibitor is cobicistat (GS-9350) or an analogue or derivative of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0019] In some embodiments, the pharmaceutical composition comprises an amount of the CYP3A4 inhibitor that effectively increases the oral bioavailability of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of the CYP3A4 inhibitor that effectively increases the C max . In some embodiments, the pharmaceutical composition comprises an amount of the CYP3A4 inhibitor that effectively increases the Cmax Increased to about 20X to about 40X, or about 25X to about 35X of C with menin administered without a CYP3A4 inhibitor. max In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively 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 a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2X to about 30X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2X to about 25X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2X to about 20X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2X to about 15X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2X to about 10X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2X to about 5X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2X to about 4X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor.

[0020] In some embodiments, the pharmaceutical composition further comprises chloropyrimidine, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibrutinib, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, daunorubicin, 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.

[0021] 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; cobicistat (GS-9350); an analogue or derivative of cobicistat (GS-9350); cyclosporine; delavirdine; diazepam → 3-OH; diethyldithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; imatinib; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; star fruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; troleandromycin; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof.

[0022] In some embodiments, the CYP3A4 inhibitor is posaconazole. In some embodiments, the CYP3A4 inhibitor is cobicistat (GS-9350) or an analogue or derivative of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0023] In some embodiments, the daily dose of the menin inhibitor is between about 10 mg and 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.

[0024] In some embodiments, the method includes an amount of a CYP3A4 inhibitor that effectively increases the oral bioavailability of the menin inhibitor. In some embodiments, the method comprises an amount of a CYP3A4 inhibitor that effectively increases the C max of the menin inhibitor. In some embodiments, the method comprises an amount of a CYP3A4 inhibitor that effectively increases the C max of the menin inhibitor to the C maxfrom about 20X to about 40X, or about 25X to about 35X. In some embodiments, the method comprises an amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor. In some embodiments, the method comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 comprises an amount of a CYP3A4 inhibitor that effectively 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 includes not significantly affecting the T of the menin inhibitor compared to T and T administered without the CYP3A4 inhibitor max and T 1 / 2 Compared to, does not significantly affect the T of the menin inhibitor max and T 1 / 2A pharmaceutical combination. 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 in parallel. 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.

[0025] Brief Description of the Drawings

[0026] Figure 1 Shows the change in steady-state AUC after oral administration of the menin inhibitor of Formula II with and without the CYP3A4 inhibitor posaconazole. Detailed Description of the Invention

[0028] The small molecule menin inhibitor administered in combination with a CYP3A4 inhibitor acts together to treat multiple diseases affecting or affected by multiple cell types.

[0029] In some embodiments, the present invention provides a combination therapy comprising a menin inhibitor and a CYP3A4 inhibitor. In some 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. In some embodiments, the present invention 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.

[0030] 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 administering a menin inhibitor in combination with a CYP3A4 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 CYP3A4 inhibitor simultaneously, separately, or sequentially.

[0031] In some embodiments, the combination therapy increases the plasma level of the menin inhibitor. In some embodiments, the combination therapy enhances the efficacy of the inhibitor in treating various 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.

[0032] 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]nonan-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]nonan-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. According to the present invention disclosed herein, the menin inhibitor is selected from Formula (I) and Formula (II)

[0033]

[0034] or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, or tautomer thereof.

[0035] Formula I is also described by the chemical name: 5-fluoro-N,N-diisopropyl-2-((4-(7-((trans-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide. Formula II is also described by the chemical name: N-ethyl-2-((4-(7-((trans-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide.

[0036] In some embodiments, the pharmaceutically acceptable salt is the bis(methanesulfonate) salt. In some embodiments, the pharmaceutically acceptable salt is the dihydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is the sesquifumarate salt.

[0037] In some embodiments, the menin inhibitor is therapeutically effective at a lower dose when combined with a CYP3A4 inhibitor. In some embodiments, the combination of the menin inhibitor and the CYP3A4 inhibitor is more effective.

[0038] 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 alvimopan, phenytoin, carbamazepine, rifampicin, enzalutamide, and St. John's wort.

[0039] 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.

[0040] 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.

[0041] The term

[0042] 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 merely exemplary and explanatory and do not limit any claimed subject matter. In this application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that, as used in the specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. In this application, unless otherwise indicated, the use of "or" means "and / or".

[0043] Furthermore, the use of the term "comprising" and other forms, such as "comprises", "containing", and "contains", is not limited.

[0044] The section headings used herein are for organizational purposes only and should not 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, manuals, and papers, are hereby expressly incorporated by reference in their entirety for any purpose.

[0045] The term "acceptable" or "pharmaceutically acceptable", as used herein with respect to a formulation, composition, or ingredient, means that it has no persistent adverse effect on the overall health of the subject being treated, or does not eliminate the biological activity or properties of the compound, and is relatively non-toxic.

[0046] "Bioavailability" refers to the percentage of the administered menin inhibitor that is delivered to the systemic circulation of a study animal or human. When administered intravenously, the total exposure of the drug (AUC(0-∞)) is typically defined as 100% bioavailability (F%). "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.

[0047] "Plasma concentration" refers to the concentration of the menin inhibitor in the plasma fraction of a subject's blood. It is understood that the plasma concentration of the 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, the blood or plasma concentration of the menin inhibitor can vary between subjects. Similarly, 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 between subjects. Due to this variability, the amount of the menin inhibitor that constitutes a "therapeutically effective amount" can vary between subjects.

[0048] As used herein, terms such as "co-administered" are meant to include the administration of a selected therapeutic agent to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0049] As used herein, the term "effective amount" or "therapeutically effective amount" means a sufficient amount of an agent or compound that is administered to alleviate to some extent one or more symptoms of a disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction of a disease symptom without undue adverse side effects. The appropriate "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein means an amount that effectively achieves the intended pharmacological effect or therapeutic improvement and the effect is without adverse side effects. It is understood that the "effective amount" or "therapeutically effective amount" varies between subjects due to the metabolism of the menin inhibitor, the age, weight, general condition of the subject, the condition being treated, 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 conventional experimentation, including but not limited to dose escalation clinical trials.

[0050] The term "enhanced" or "enhancement" means an increase or prolongation in the potency or duration of an intended effect. For example, "enhancing" the effect of a therapeutic agent means the ability to increase or prolong the potency or duration of the therapeutic agent during the treatment of a disease, disorder, or condition. As used herein, an "enhancing effective amount" means an amount sufficient to enhance the effect of a therapeutic agent in the treatment of a disease, disorder, or condition. When used in a patient, the amount effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health status and response to the drug, and the judgment of the treating physician. The terms "subject", "patient", and "individual" are used interchangeably. As used herein, they refer to an animal. By way of example only, a subject can be, but is not limited to, a mammal, including but not limited to a human. These terms do not require the supervision (either continuous or intermittent) of a medical professional.

[0051] As used herein, the terms "treat", "treating", or "treatment" include alleviating, reducing, or relieving the symptoms of a disease or condition, preventing additional symptoms, alleviating or preventing the underlying metabolic causes of the symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, ameliorating the disease or condition, causing regression of the disease or condition, alleviating the condition 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 management.

[0052] As used herein, IC50 refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition (e.g., inhibition of menin) of the maximal response in an assay measuring said response.

[0053] As used herein, EC50 refers to the amount, concentration, or dose 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.

[0054] A variety of pharmaceutically acceptable salts are formed from menin inhibitors and include: acid addition salts formed by the reaction of menin with organic acids, which include aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic 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 by the reaction of a menin inhibitor with inorganic acids, which include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0055] The term "pharmaceutically acceptable salt" refers to salts of menin inhibitors that do not cause significant irritation to the administered mammal and do not substantially eliminate the biological activity and properties of the compound.

[0056] It is to be understood that reference to pharmaceutically acceptable salts includes solvate addition forms (solvates). Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during product formation or separation from a pharmaceutically acceptable solvent, such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In one aspect, solvates are formed using, but not limited to, 3 classes of solvents. The classes of solvents are defined, for example, in the 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 or pharmaceutically acceptable salts of menin inhibitors can be conveniently prepared or formed during the processes described herein. In some embodiments, the solvates of menin inhibitors are anhydrous. In some embodiments, the menin inhibitor or its pharmaceutically acceptable salt exists in a non-solvated form. In some embodiments, the menin inhibitor or its pharmaceutically acceptable salt exists in a non-solvated form and is anhydrous.

[0057] In other embodiments, the menin inhibitor or its pharmaceutically acceptable salt is prepared in various forms, including but not limited to amorphous phase, crystalline form, milled form, and nanoparticle form. In some embodiments, the menin inhibitor or its pharmaceutically acceptable salt is amorphous. In some embodiments, the menin inhibitor or its pharmaceutically acceptable salt is amorphous and anhydrous. In some embodiments, the menin inhibitor or its pharmaceutically acceptable salt is crystalline. In some embodiments, the menin inhibitor or its pharmaceutically acceptable salt is crystalline and anhydrous.

[0058] General CYP3A inhibitor

[0059] In certain embodiments, drug combinations comprising a menin inhibitor and a CYP3A inhibitor are disclosed herein. In certain embodiments, combinations of a pharmaceutical composition comprising a menin inhibitor and a CYP3A inhibitor of a pharmaceutical composition are further disclosed herein.

[0060] 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 cholesterol, steroid, and other lipid synthesis. The CYP3A cluster consists of four genes; CYP3A4, CYP3A5, CYP3A7, and CYP3A43.

[0061] Cytochrome P450 enzymes modify a variety of substrates, including hydroxylation, epoxidation, aromatic oxidation, heteroatom oxidation, N- and O-dealkylation, aldehyde oxidation, and dehydrogenation.

[0062] In some embodiments, a menin inhibitor and a CYP3A inhibitor are co-administered in parallel (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially.

[0063] In some embodiments, a menin inhibitor and a CYP3A inhibitor are co-administered in separate dosage forms. In some embodiments, a menin inhibitor and a CYP3A inhibitor are co-administered in a combined dosage form.

[0064] In some embodiments, co-administration of a menin inhibitor inhibitor and a CYP3A inhibitor increases the oral bioavailability of the menin inhibitor. In some embodiments, co-administration of a menin inhibitor inhibitor and a CYP3A inhibitor increases the C of the menin inhibitor max . In some embodiments, co-administration of a menin inhibitor and a CYP3A inhibitor increases the AUC of the menin inhibitor. In some embodiments, co-administration of a menin inhibitor and a CYP3A inhibitor increases the T of the menin inhibitor 1 / 2 .

[0065] 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 before the menin protein inhibitor. In some embodiments, the CYP3A4 inhibitor is administered before the menin protein inhibitor. In some embodiments, the CYP3A4 inhibitor is posaconazole and is administered before the menin inhibitor of formula II.

[0066] In some embodiments, a menin inhibitor and a CYP3A inhibitor are administered in temporal proximity (e.g., the menin inhibitor and the CYP3A inhibitor can initially be administered simultaneously). 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 before or after the administration of another therapeutic agent such that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of the other agent. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent.

[0067] In some embodiments, "in temporal proximity" means administering one therapeutic agent within a period of time before or after the administration of another therapeutic agent such that there is a synergistic effect between one therapeutic agent and the other therapeutic agent. "In temporal proximity" can vary due to various factors, including but not limited to the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is to be administered; the disease or condition to be treated or alleviated; the therapeutic outcome to be achieved; the dose, dosing frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration of the therapeutic agent. In some embodiments, "in temporal proximity" means within 15 minutes, within 30 minutes, within one hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within one week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be in temporal proximity to a single administration of another therapeutic agent. In some embodiments, in temporal proximity can vary during a treatment cycle or within a dosing regimen.

[0068] "Combination therapy" is intended to include administering the therapeutic agents disclosed herein in a sequential or simultaneous manner, where each therapeutic agent is administered at a different time, and administering these therapeutic agents or at least two of them in parallel or in substantially simultaneous manner. For example, simultaneous administration can be achieved by administering to a subject a single capsule having a fixed or variable ratio of each therapeutic agent or multiple single capsules of each therapeutic agent. The sequential or substantially simultaneous administration of each therapeutic agent can be affected by any suitable route, including but not limited to oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or different routes. For example, the 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.

[0069] 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 contact each other in a human body (e.g., only in a human body). In some embodiments, the present disclosure provides a method for preparing a combination therapy by contacting a menin inhibitor and a CYP3A inhibitor with each other at a site. In some embodiments, the method for preparing a combination therapy by contacting a menin inhibitor and a CYP3A inhibitor with each other at a site occurs in a human body (e.g., only in a human body).

[0070] As 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.

[0071] Combination with a CYP3A4 inhibitor

[0072] In certain embodiments, the present disclosure discloses a combination comprising a menin inhibitor and a CYP3A4 inhibitor.

[0073] In certain embodiments, the present disclosure further discloses a pharmaceutical combination comprising a menin inhibitor and a CYP3A4 inhibitor.

[0074] Cytochrome P450 3A4 (abbreviated as CYP3A4) (EC 1.14.13.97) is a member of the cytochrome P450 mixed-function oxidase system. The cytochrome P450 protein is a monooxygenase that catalyzes many reactions in drug metabolism. CYP3A4 is encoded by the CYP3A4 gene. This gene is part of the cytochrome P450 gene cluster on chromosome 7q21.1. CYP3A4 is involved in the oxidation of a large number of substrates, such as menin inhibitors.

[0075] Cytochrome P450 enzymes modify a variety of substrates, including hydroxylation, epoxidation, aromatic oxidation, heteroatom oxidation, N- and O-dealkylation, aldehyde oxidation, and dehydrogenation.

[0076] In some embodiments, the menin protein inhibitor and the CYP3A4 inhibitor are co-administered in parallel (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially.

[0077] In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are co-administered in separate dosage forms. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are co-administered in a combined dosage form.

[0078] In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the oral bioavailability of the menin inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max . In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor.

[0079] In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of the menin inhibitor administered without a CYP3A4 inhibitor by about 20X to about 40X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max by about 25X to about 35X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 20X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 21X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 22X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 23X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 24X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 25X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 26X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 27X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 28X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein by about 29X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C max of menin protein bymax Approximately 30X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 30X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 32X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 33X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 34X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 35X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 36X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 37X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 38X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 39X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the C of menin protein max Approximately 40X.

[0080] In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 15X to about 35X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 20X to about 30X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 35X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 30X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 25X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 20X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 15X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 10X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 5X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 4X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 15X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 3X. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 4X.In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 5 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 6 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 7 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 8 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 9 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 10 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 11 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 12 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 13 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 14 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 15 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 16 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 17 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 18 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 19 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 20 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 21 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 22 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 23 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 24 - fold.In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 25 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 26 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 27 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 28 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 29 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 30 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 31 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 32 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 33 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 34 - fold. In some embodiments, co - administration of a menin inhibitor and a CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 35 - fold.

[0081] Any suitable daily dose of a CYP3A4 inhibitor can be used with the compositions, dosage forms, and methods disclosed herein. For example, the daily dose of a CYP3A4 inhibitor depends on the potency of the CYP3A regulator inhibitor. A weak CYP3A4 inhibitor (such as cimetidine) will require a higher daily dose than a moderate CYP3A4 inhibitor (such as erythromycin, grapefruit juice, verapamil, diltiazem), and a moderate CYP3A4 inhibitor requires a higher daily dose than a strong CYP3A4 inhibitor (such as indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone).

[0082] Exemplary CYP3A4 inhibitors

[0083] In some embodiments, a menin inhibitor is co - administered with a CYP3A4 inhibitor selected from: anti - arrhythmic agents; anti - histamines; azole antifungals; benzodiazepines; calcium channel blockers; HIV antivirals; HMG CoA reductase inhibitors; macrolide antibiotics; prokinetics; protease inhibitors; or any combination thereof.

[0084] In some embodiments, 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. US2005 / 0209301 and U.S. Patent Publication No. US2005 / 0267074. In some embodiments, 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.

[0085] 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; cobicistat (GS-9350); analogs or derivatives 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; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; star fruit; 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 cobicistat (GS-9350) or an analog or derivative of cobicistat (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-hydroxy diazepam and quinidine → 3-OH refers to 3-hydroxy quinidine. In some embodiments, the CYP3A4 inhibitor is a pharmaceutically acceptable salt of one or more of those listed above or below.

[0086] Any suitable CYP3A4 inhibitor is contemplated for use with the compositions, dosage forms, and methods disclosed herein. The choice of CYP3A4 inhibitor depends on a variety of factors. For example, factors to be considered include the desired reduction in the 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 cases, the CYP3A4 inhibitor is a CYP3A4 inhibitor that can be taken for a long period of time (e.g., chronically). In some embodiments, the CYP3A4 inhibitor is taken for a limited time, and the menin inhibitor is taken chronically.

[0087] In certain embodiments, methods of increasing the C max of a menin inhibitor are disclosed herein, including co-administering a combination of menin protein and a CYP3A4 inhibitor. In some embodiments, the C max of the menin inhibitor is increased as compared to the C maxfrom about 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 a 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 a 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 a 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 a 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 a 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 a 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 a 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 a 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 a CYP3A4 inhibitor.

[0088] In certain embodiments, methods for increasing the AUC of a menin inhibitor are disclosed herein, including administering a combination of a menin protein and a CYP3A4 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, 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 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 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 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 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 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 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 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 the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the C of the menin inhibitor max . In some embodiments, the C of the menin inhibitor max is increased to about 20X to about 40X, or about 25X to about 35X, the C of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, compared to the T max or T max of the menin inhibitor administered without the CYP3A4 inhibitor, the method does not significantly affect the T 1 / 2 or T max of the menin inhibitor 1 / 2 .

[0089] Method used

[0090] In some embodiments, it is a method of treating cancer in an individual in need thereof, comprising administering a combination of a menin inhibitor and a CYP3A4 inhibitor. Accordingly, the combinations and methods of the present invention are considered effective against a wide range of cancers, including but not limited to hematological cancers (e.g., leukemia and lymphoma), 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), kidney cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., papillary thyroid 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 depends on the MLL gene. In some embodiments, the MLL gene is MLL1. In some embodiments, the cancer is associated with a gain-of-function mutation of p53.

[0091] In some embodiments, specific 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, bronchioloalveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, bronchial adenoma / carcinoid, and pleuropulmonary blastoma; gastrointestinal cancers, including, for example, cancers of the esophagus (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), stomach (e.g., carcinoma, lymphoma, and leiomyosarcoma), pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, and vipoma), small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), 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, appendiceal 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 cancers, including, for example, cancers of the kidney (e.g., adenocarcinoma, nephroblastoma (Wilms' tumor), lymphoma, and leukemia), bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), prostate (e.g., adenocarcinoma and sarcoma), testis (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma), as well as transitional cell carcinoma, transitional cell cancers of the renal pelvis and ureter and other urinary organs, urethral cancer, and bladder cancer; liver cancers, including, for example, liver cancer (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, osteochondroma (exostosis), benign chondroma, 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 Paget's disease); cancers of the meninges (such as meningioma, meningeal sarcoma, and gliomatosis); cancers of the brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors);Cancers of the spinal cord (such as neurofibroma, meningioma, glioma, and sarcoma) and other nervous system cancers (such as brainstem 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, pineoblastoma, and supratentorial primitive neuroectodermal tumor); gynecological cancers, including, for example, cancers of the uterus (such as endometrial cancer), cervix (such as cervical cancer and precancerous cervical dysplasia), ovaries (such as ovarian cancer, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumor, Sertoli Leydig cell tumor, dysgerminoma, and malignant teratoma), vulva (such as squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), vagina (such as clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides, and embryonal rhabdomyosarcoma), and fallopian tube (such as carcinoma); other genital tract cancers, including, for example, endometrial cancer, endometrial carcinoma of the uterus, germ cell tumor, gestational trophoblastic tumor, gestational trophoblastic neoplasm glioma, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumor, extragonadal germinoma, uterine cancer, corpus cancer of the uterus, uterine sarcoma; lymphatic and blood cancers, including, for example, cancers of the blood (such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndrome, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenstrom macroglobulinemia) and other lymphatic or blood cancers, including, for example, childhood leukemia, myeloproliferative disorders (such as primary myelofibrosis), plasma cell tumor / multiple myeloma, myelodysplasia, myelodysplastic syndrome, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymoma and thymic carcinoma, mycosis fungoides, and Sézary syndrome; skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, Merkel cell carcinoma, Merkel cell skin cancer, melanoma, and carcinoid; adrenal cancer, including, for example, neuroblastoma; other cancers related to the endocrine system, including, for example, adrenocortical carcinoma, multiple endocrine neoplasia (such as multiple endocrine neoplasia type I), multiple endocrine neoplasia syndrome, parathyroid carcinoma, pituitary tumor, pheochromocytoma, pancreatic islet cell carcinoma, and pancreatic islet cell tumor); connective tissue cancer (such as 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, oral cancer, laryngeal cancer, esophageal cancer, throat cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oral cancer, oropharyngeal 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.;

[0092] In some embodiments, the cancer is a hematological cancer, such as leukemia or lymphoma. Exemplary leukemias and lymphomas treatable with the compounds of the present invention include mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated 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 lymphocytic leukemia or acute lymphoblastic leukemia), acute myeloid leukemia (AML) (also known as acute myelogenous leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also known as chronic lymphocytic leukemia), chronic myelogenous leukemia (CML) (also known as chronic myeloid leukemia), therapy-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (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 mycosis, Sézary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocyte leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenstrom macroglobulinemia. In some embodiments, acute myeloid leukemia (AML) is acute myeloid (i.e., NPM1 mut acute myeloid) leukemia.

[0093] In certain embodiments, the compounds of the invention are used for the treatment of leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic lymphoma associated with MLL rearrangement, acute lymphocytic leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, acute myelocytic leukemia associated with MLL rearrangement or acute myeloblastic leukemia associated with MLL rearrangement. As used herein, "MLL rearrangement" refers to the rearrangement of the MLL gene.

[0094] 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; cobicistat (GS-9350); an analogue or derivative of cobicistat (GS-9350); cyclosporine; delavirdine; diazepam → 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; imatinib; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; star fruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; troleandromycin; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is cobicistat (GS-9350) or an analogue or derivative of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0095] In some embodiments, the method increases the C of the menin inhibitor max . In some embodiments, the C of the menin inhibitor max is increased to the C of the menin inhibitor administered without a CYP3A4 inhibitor maxfrom about 20X to about 40X, or from 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 a 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 a 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 a 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 a 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 a 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 a 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 a 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 a 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 a CYP3A4 inhibitor. In some embodiments, compared to T max and T 1 / 2 administered without a CYP3A4 inhibitor, the method does not significantly affect the T max and T 1 / 2。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 in parallel. 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 chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibrutinib, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the method further comprises co-administering cyclophosphamide, daunorubicin, 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.

[0096] Malignant lymphoma is the neoplastic transformation of cells mainly present in lymphoid tissue. Two groups of malignant lymphomas are Hodgkin lymphoma and non-Hodgkin malignant lymphoma (NHL). Both types of lymphoma infiltrate reticuloendothelial tissue. However, they differ in the tumor cells of origin, the site of the disease, the presence of systemic symptoms, and the response to treatment ((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)).

[0097] The combination can also be used to treat leukemia patients with MLL / KMT2A gene rearrangement.

[0098] Leukemia

[0099] 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, it is a method of treating leukemia in an individual in need thereof, comprising: administering a pharmaceutical composition comprising a menin inhibitor and a pharmaceutical composition comprising a CYP3A4 inhibitor.

[0100] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually white blood cells (leukocytes). Leukemia is a broad term encompassing a variety of diseases. The first is the acute and chronic forms: (i) Acute leukemia is characterized by a rapid increase in 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 into the bloodstream and spread to other organs of the body. The acute form of leukemia is the most common form of leukemia in children; (ii) Chronic leukemia is distinguished by the excessive accumulation 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 mainly occurs in the elderly, but can theoretically 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 myeloid or myelogenous leukemia: (i) Lymphoblastic or lymphocytic leukemia, where the cancerous change occurs in a type of bone marrow cell that normally forms lymphocytes, which are immune system cells that fight infection; (ii) Myeloid or myelogenous leukemia, where 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.

[0101] 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).

[0102] The symptoms, diagnostic tests, and prognostic tests for each of the above conditions are known. See, for example, Harrison's Principles of Internal "16th Edition, 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).

[0103] A number of animal models can be used to establish a range of therapeutically effective doses of inhibitor compounds, such as menin inhibitors, for treating any of the foregoing diseases.

[0104] During treatment, the therapeutic efficacy of a menin inhibitor against any of the foregoing diseases can be optimized. For example, a subject being treated can undergo diagnostic evaluations to correlate remission of disease symptoms or pathology with inhibition of in vivo menin activity achieved by administering a given dose of the menin inhibitor. Cellular assays known in the art can be used to determine in vivo activity. Accordingly, the amount of the menin inhibitor compound administered to the subject can be increased or decreased as needed to maintain an optimal level of menin inhibition for treating the subject's disease state.

[0105] In some embodiments, a menin inhibitor and a CYP3A4 inhibitor are used in the preparation of a medicament for treating any of the foregoing conditions. In some embodiments, the combination of the present invention relates to the treatment of leukemia. In some embodiments, the present invention relates to treating leukemia in a patient in need thereof, including administering a menin inhibitor and a CYP3A4 inhibitor. In some further embodiments, the present invention relates to treating leukemia in a patient in need thereof, including administering a pharmaceutical composition comprising a menin inhibitor and a pharmaceutical composition comprising a CYP3A4 inhibitor. In some further embodiments, the present invention relates to treating leukemia in a patient in need thereof, including administering a pharmaceutical composition comprising a menin inhibitor of formula I and a pharmaceutical composition comprising an azole antifungal CYP3A4 inhibitor.

[0106] Acute leukemia is usually caused by acquired mutations in hematopoietic progenitor cells. Chromosomal abnormalities are often discrete mutational features of leukemia. Many of these chromosomal abnormalities are due to specific translocations that result in the formation of fusion genes, which become drivers of tumorigenesis and tumor development. A specific example involves the MLL1 gene. Translocations of the MLL1 locus (11q23) can lead to the formation of oncogenic fusions characteristic of MLLr acute leukemia. The MLL1 protein is a key regulator of development and is the mammalian homolog of the Drosophila trithorax. It is an important epigenetic regulator of HOX gene expression. Translocations of the MLL1 locus generate chimeric proteins that fuse the N-terminus of MLL1 to variable C-terminal domains from different translocation partners. More than 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 inhibits differentiation and enhances proliferation, leading to MLLr acute leukemia. Conventional diagnosis using fluorescence in situ hybridization (FISH) involves translocations of the MLL1 locus (11q23). Depending on the progenitor cell of origin, MLLr can present as ALL, AML, or mixed phenotype acute leukemia (MPAL). These translocations are rare, with an overall annual incidence of ~4,000 cases in the United States, Europe, and Japan. Approximately 10% of all leukemias have an MLL1 translocation.

[0107] This combination can also be used to treat leukemia patients with MLL / KMT2A gene rearrangements.

[0108] Patients with MLLr have a high risk of relapse after conventional chemotherapy and stem cell transplantation, with an overall 5-year survival rate of only about 35%. There is currently no specific targeted therapy for MLLr leukemia. The combination of a menin inhibitor of Formula I or Formula II with a CYP3A4 inhibitor can provide a new targeted therapy for MLLr acute leukemia.

[0109] Treatment of relapsed or refractory MLLr acute leukemia

[0110] The interaction between the MLL1 fusion protein and 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. Binding of the MLL1 fusion to menin is mediated by amino acid residues 9 - 13 (FPARP) at the N-terminus of MLL1. Binding to menin localizes these fusions to chromatin, thereby initiating a leukemic transcriptional program, including upregulation of the HOXA locus and the MEIS1 gene. The interaction between the fusion protein and menin is required to maintain this transcriptional program.

[0111] Menin inhibitors of formula I or formula II bind to the MLL1 binding pocket on menin with high affinity 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 the MLL1 fusion proteins required for leukemic activity, thereby impairing the expression of key oncogenes, resulting in growth arrest and inhibition of cell proliferation. Small molecule inhibitors of the menin-MLL interaction have been reported. These inhibitors have shown antiproliferative activity against MLLr cell lines and have shown single-dose survival benefits in MLLr leukemia mouse models.

[0112] Similarly, combining a menin inhibitor of formula I or formula II with a CYP3A4 inhibitor increases efficacy, shows potent activity in multiple leukemia xenograft models, and provides profound survival benefits after oral administration in non-clinical models. Collectively, these data suggest that pharmacological inhibition of the menin-MLL interaction is a potential targeted strategy for the treatment of MLLr acute leukemia.

[0113] NPM1c AML

[0114] AML is an acute leukemia characterized by the accumulation of myeloid cells in the bone marrow due to impaired differentiation and proliferation. NPM1 is one of the most commonly mutated genes in AML. Point mutations in the NPM1 gene result in abnormal cytoplasmic localization of the mutant protein, called NPM1c. The identification of NPM1c is an important part of the diagnostic screening for AML. Only AML patients with a mutated NPM1 have a good prognosis, with a five-year overall survival (OS) of ~60%. However, most (>80%) NPM1c AML patients have multiple concurrent mutations, which may have an adverse impact on prognosis. Co-mutations have been found in the FLT3, DNMT3A, NRAS, TET2, and IDH1 / 2 genes. NPM1c is not usually seen in ALL.

[0115] 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 carrying NPM1c have been found to be highly sensitive to menin-MLL interaction inhibitors, combining a menin inhibitor of formula I or formula II with a CYP3A4 inhibitor could provide a new targeted therapy for NPM1c AML.

[0116] Treatment of NPM1c AML patients

[0117] NPM1 normally exists between the nucleus and cytoplasm as a nucleolar protein. It has multiple functions, including the assembly and transport of ribosomal proteins, the control of centrosome replication, and the regulation of the tumor suppressor ARF. The cytoplasmic localization of the mutant NPM1c results in the abnormal distribution of NPM1c-associated nuclear proteins into the cytoplasm, including several transcription factors. These include PU.1, a major driver of monocyte lineage differentiation. The loss of PU.1 from the nucleus in NPM1c AML leads to the repression of >500 terminal differentiation genes. The inhibition of differentiation by NPM1c enables the leukemic transcriptional program to be highly dependent on the upregulated expression of the HOXA cluster and MEIS1 genes. The expression of these genes further blocks differentiation and induces long-term proliferation, resulting in the leukemic phenotype.

[0118] In addition, the HOX / MEIS signature of NPM1c AML overlaps with that of MLLr leukemia and hematopoietic stem cells (HSCs). The maintenance of this transcriptional signature in NPM1c cells directly depends on the menin-MLL1 interaction.

[0119] Although little is known about how mutant NPM1c cells maintain abnormal gene expression, mutations in the menin-binding motif of MLL1 have been shown to strongly inhibit the proliferative capacity of NPM1c due to the loss of binding of MLL1 to menin. In addition, the small molecule menin-MLL interaction inhibitor MI-503 has been shown to inhibit the HOXA / MEIS1 transcriptional program in NPM1c cells, leading to growth arrest, terminal differentiation, and cell death, confirming the crucial role of the menin-MLL1 interaction in NPM1c. These findings were validated and extended in another report, which demonstrated that the orally active menin inhibitor KO-539 has potent anti-leukemic activity in an NPM1c mutant AML patient-derived xenograft model. Collectively, these results suggest that cells carrying NPM1c are highly sensitive to menin-MLL interaction inhibitors.

[0120] In some embodiments, the combination of the present invention is used to treat NMP1 AML. In some embodiments, the present invention relates to treating NMP1 AML in a patient in need thereof, including administering a menin inhibitor and a CYP3A4 inhibitor. In some further embodiments, the present invention relates to treating NMP1 AML in a patient in need thereof, including administering a pharmaceutical composition comprising a menin inhibitor and a pharmaceutical composition comprising a CYP3A4 inhibitor. In some further embodiments, the present invention relates to treating NMP1 AML in a patient in need thereof, including administering a pharmaceutical composition comprising a menin inhibitor of formula I and a pharmaceutical composition comprising an azole antifungal CYP3A4 inhibitor.

[0121] Other combination therapies

[0122] In certain cases, it is appropriate to administer a menin inhibitor and a CYP3A4 inhibitor in combination with other therapeutic agents. In certain cases, it is appropriate to administer a menin inhibitor and a CYP3A4 inhibitor in combination with additional CYP3A4 inhibitors. The additional therapeutic agents are selected for their particular utility in the condition being treated. Generally, it is not necessary to administer the additional therapeutic agents in the same pharmaceutical composition, simultaneously or by the same route, as the menin inhibitor and / or the CYP3A4 inhibitor. In some embodiments, an initial administration is made according to an established protocol, and then, based on the observed effects, the dosage, mode of administration, and timing of administration are further modified.

[0123] In some embodiments, the additional therapeutic agents are administered either concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, the condition of the patient, and the actual selection of the compounds used. In certain embodiments, the order of administration and the number of administration repetitions of each therapeutic agent during the treatment protocol are determined based on an assessment of the disease being treated and the patient's condition.

[0124] The dosage of the additional therapeutic agent varies depending on the additional therapeutic agent, the disease or condition being treated, and the like.

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

[0126] In certain embodiments, methods for treating an autoimmune disorder, a xenimmune disorder, an inflammatory disorder, and / or cancer in an individual in need thereof are disclosed herein, comprising administering to the individual a menin inhibitor, a CYP3A4 inhibitor, and an additional therapeutic agent. In certain embodiments, methods for treating an autoimmune disorder in an individual in need thereof are further disclosed herein, comprising administering to the individual a menin inhibitor, a CYP3A4 inhibitor, and an additional therapeutic agent. In certain embodiments, methods for treating a xenimmune disorder in an individual in need thereof are also disclosed herein, comprising administering to the individual a menin inhibitor, a CYP3A4 inhibitor, and an additional therapeutic agent. In certain embodiments, methods for treating an inflammatory disorder in an individual in need thereof are disclosed herein, comprising administering to the individual a menin inhibitor, a CYP3A4 inhibitor, and an additional therapeutic agent. In certain embodiments, methods for treating cancer in an individual in need thereof are further disclosed herein, comprising administering to the individual a menin inhibitor, a CYP3A4 inhibitor, and an additional therapeutic agent.

[0127] In some embodiments, administering a menin inhibitor prior to a second cancer treatment regimen reduces an immune-mediated response to the second cancer treatment regimen. In some embodiments, administering a menin inhibitor prior to ofatumumab reduces an immune-mediated response to ofatumumab.

[0128] 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, radioimmunotherapy, a DNA damaging agent, a proteasome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jak l / 2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.

[0129] In some embodiments, the additional therapeutic agent is chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibrutinib, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

[0130] In some embodiments, the additional therapeutic agent is cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab. In some embodiments, the additional therapeutic agent is bendamustine and rituximab. In some embodiments, the additional therapeutic agent comprises 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

[0131] 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, clofarabine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trofosfamide; alkyl sulfonates such as busulfan, mannomustine, treosulfan; ethylenimines such as carboquone, thiotepa, triaziquone; nitrosoureas such as carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; epoxides such as etoglucid; other alkylating agents such as dacarbazine, mitobronitol, pipobroman, temozolomide; folic acid analogs such as methotrexate, pemetrexed, pralatrexate, raltitrexed; purine analogs such as cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, thioguanine; pyrimidine analogs 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; taxanes such as docetaxel, paclitaxel, paclitaxel poliglumex; other plant alkaloids and natural products such as trabectedin; actinomycins such as dactinomycin; anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorubicin; other cytotoxic antibiotics such as bleomycin, elsamitrucin, mitomycin, rugulosin; platinum compounds such as carboplatin, cisplatin, oxaliplatin, satraplatin; methylhydrazines such as procarbazine; sensitizers such as aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfin; protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, temsirolimus; other antineoplastic agents such as acitretin, atretamine, azacrin, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxyurea, irinotecan, lonidamine, masoprocol, miltefosine, mitoguazone, mitotane, oblimersen, pegaspargase, tebuconazole, romidepsin, sitimagene ceradenovec, tiazofurin, topotecan, tretinoin, vorinostat;Estrogens, such as diethylstilbestrol, ethinylestradiol, estriol, polyestradiol phosphate;

[0132] Progestogens, such as progesterone, medroxyprogesterone, megestrol acetate; gonadotropin-releasing hormone analogs, such as buserelin, goserelin, leuprorelin, 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, mifamurtide, pidotimod, prazopriv, roquinimex, thymopentin; immunosuppressants, such as everolimus, gusperimus, leflunomide, mycophenolic acid, sirolimus; calcineurin inhibitors, such as cyclosporine, tacrolimus; other immunosuppressants, such as azathioprine, lenalidomide, methotrexate, thalidomide; and radiopharmaceuticals, such as iobenguane.

[0133] Other therapeutic agents that can be administered in combination with the combination of menin inhibitors and CYP3A4 inhibitors include, but are not limited to, interferons, interleukins, tumor necrosis factors, growth factors, etc.

[0134] 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 ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, and sargramostin; interferons such as interferon α-natural, interferon a-2a, interferon α-2b, interferon α-1, interferon α-nl, interferon β-natural, interferon β-la, interferon β-lb, interferon γ, pegylated interferon α-2a, pegylated interferon α-2b; interleukins such as interleukin, oravelkin; other immunostimulants such as BCG vaccine, glatiramer acetate, dihydrohistamine, immunochromogen, lentinan, melanoma vaccine, mifamurtide, pegylated enzyme, pidotimod, pulisavir, poly I:C, poly ICLC, roquinimex, tasocitinib, thymopentin; immunosuppressants such as abatacept, abetimus, alefacept, antilymphocyte immunoglobulin (equine), antithymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muromab-CD3, mycophenolic acid, natalizumab, sirolimus; TNFα inhibitors such as adalimumab, afelimomab, certolizumab, etanercept, golimumab, infliximab; interleukin inhibitors such as anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, ustekinumab; calcineurin inhibitors such as cyclosporine, tacrolimus; other immunosuppressants such as azathioprine, lenalidine, methotrexate, thalidomide.

[0135] 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, etc. or combinations thereof.

[0136] Additional therapeutic agents that can be administered in combination with a 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, immunosuppressive agents, eculizumab, efalizumab, muromonab-CD3, natalizumab; TNF-α 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, conatumab, dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresoliumab, galiximab, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab, inotuzumab ozogamicin, ipiliumab, lexatuumab, lintuzumab, lintuzumab, lucatumab, mapatummab, matuzumb, milatuzumab, monoclonal antibody CC49, nectumab, nimotuzumab, ofatumab, oregovomab, pertuzumab, ramacurimab, ranibumab, siplizumab, sonepcizumab, tanezumab,Tositumomab, trastuzumab, tremelimumab, tucotuzumab celmoleukin, veltuzumab, visilizumab, volociximab, zalutuumab.

[0137] 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, agents that affect the tumor microenvironment, such as cell 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 PKCγ inhibitor, such as enzastaurin by way of example only.

[0138] Examples of agents that affect the tumor microenvironment include PI3K signaling inhibitors, syc kinase inhibitors, protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, temsirolimus; other angiogenesis inhibitors such as GT-111, JI-101, R1530; other kinase inhibitors such as AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD28055, AZD 8931, baricitinib, 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, progenitor cell factor, 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.

[0139] 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 (such as rituximab).

[0140] Other reagents that can be used in combination with menin inhibitors and CYP3A4 inhibitors include, but are not limited to, doxorubicin, dacomycin, bleomycin, vinblastine, cisplatin, acyclovir; aclarubicin; adozelesin hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cefedipine; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate;Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Iimofosine; Interleukin II (including recombinant interleukin II or rIL2), Interferon α-2a; Interferon α-2b; Interferon α-n1; Interferon α-n3; Interferon β-1a; Interferon γ-1b; Isopropylmolybdenum; 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; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; 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.;

[0141] 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, 20-epi-1,25-dihydroxyvitamin D3; 5-ethyluracil; abiraterone; aclarubicin; acylfluorene; adecypenol; adozelene; aldesleukin; ALL-TK antagonist; taurine; ambamustine; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antileukotriene; anti-transforming morphogenetic protein-1; antiandrogen, prostate cancer; antiestrogen; antineoplastic agent; antisense oligonucleotide; glycinoeclepin; apoptosis gene regulator; apoptosis regulator; azapurinic acid; ara-CDP-DL-PTBA; arginine deiminase; picric acid; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivative; balanol; batimastat; BCR / ABL antagonist; benzoporphyrin; benzoylstarfish toxin; beta-lactam derivative; beta-alethine; beta-clamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyl spermine; bisnafide; bistratene A; bizelesin; breflate; bromopirimine; budotitane; buthionine; calcipotriol; calphostin C; camptothecin derivative; canarypox IL-2; capecitabine; carbamoyl aminotriazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogue; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; clinatoprost; cryptophycin 8; cryptophycin A derivative; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; cytarabine octadecylphosphate; cytolytic cytokine; hexestrol phosphate; dacliximab; decitabine; dehydrorotenone B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dextroverapamil; diaziquone; rotenone B; didox;Diethylnorspermine; Dihydro-5-azacytidine; 9-dioxamycin; Diphenylspirostatin; Docetaxel; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Carcinomycin SA; Ebselen; Ifomustine; Edelfosine; Idecabtagene; Eflornithine; Elemen; Emitefur; Epirubicin; Epristeride; Estramustine analogue; Estrogen agonist; Estrogen antagonist; Etazolate; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Flunisolide; Fluasterone; Fludarabine; Fluorodaunorunicin hydrochloride; Formestane; Fostriecin; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitor; Gemcitabine; Glutathione inhibitor; Hepsulfam; Heregulin; Hexamethyl bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idomene; Imafostin; Ilomastat; Imidazoacridone; Imiquimod; Immunostimulatory peptide; Insulin such as growth factor-1 receptor inhibitor; Interferon agonist; Interferon; Interleukin; Iobenguane; Iodoxorubicin; 4-Ipomoeamarine; Iropramide; Isolaidine; Isobengazole; Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Discodermolide triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprorelin + estrogen + progesterone; Leuprolide; Levamisole; Liaziol; Linear polyamine analogue; Lipophilic disaccharide peptide; Lipophilic uranium compound; Lissoclinamide 7; Lobaplatin; Lombricine; Lomtrexol; Lonidamine; Losoxantrone; Lovastatin; Losoxuridine; Letotecan; Lutetium texaphyrin; Lysofylline; Lytic peptide; Mertansine; Tallysomycin A; Marimastat; Masoprocol; Maspin; Matrix metalloproteinase inhibitor; Menogaril; Merbarone; Metreleptin; Methioninase; Metoclopramide; MIF inhibitor; Mifepristone; Miltefosine; Miltiromycin; Mismatched double-stranded RNA; Mitoguazone; Mitobronitol; Mitomycin analogue; Mitonafide; Mitotoxin fibroblast growth factor-saponin; Mitoxantrone; Mofarotene; Molgramostim; Monoclonal antibody, human chorionic gonadotropin; Monophosphoryl lipid A + Mycobacterium cell wall sk; Monordinol; Multidrug resistance gene inhibitor; Therapy based on multiple tumor suppressor 1; Mustard anticancer agent;Indian Ocean sponge B (mycaperoxide B); Mycobacterium cell wall extract; myriaporone; N-acetyl dinatrenone; N-substituted benzamide; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide regulator; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; omapatrilat; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoyl rhizoxin; pamidronic acid; panaxatriol; panomifene; paracoccusin; pazelliptine; pegaspargase; pefloxacin; pentosan polysulfate sodium; pentostatin; pentrozole; perfluorobromooctane; peplomycin; perilla alcohol; phenylazomycin; phenyl acetate; phosphatase inhibitor; streptolysin; pilocarpine hydrochloride; pirarubicin; pirroxantrone; pestacin A; pestacin B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bisacridone; prostaglandin J2; proteasome inhibitor; protein A-based immunomodulator; protein kinase C inhibitor; microalgal protein kinase C inhibitor; protein tyrosine phosphatase inhibitor; purine nucleoside phosphorylase inhibitor; purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; demethylated retipiptine; rhenium-186 hydroxyethylidene diphosphonate; rhizoxin; ribozyme; RII retinamide; rhothionine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; SarCNU; saintopin; sarcophytol A; sargramostim; Sdi 1 mimic; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin-binding protein; sonermin; phosphonasp; spicamycin D; spirofosfamide; spleen pentapeptide; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; matrix metalloproteinase inhibitor; sulfinosine; super-potent vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycan; tamoxifen; tamoxifen methiodide; tauromustine; tazarotene; ticagrelan sodium; tegafur; tellurapyrylium; telomerase inhibitorTemoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thioblastin; thiophene; thrombopoietin; thrombopoietin mimetics; thymofasin; thymopoietin receptor agonist; thymosin; thyroid-stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanium dichloropentadienyl; topsentin; toremifene; totipotent stem cell factor; transformation inhibitor; retinoic acid; tyrosine kinase inhibitor; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; torosterol; tyrosine kinase inhibitor; tyrphostins; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonist; vapreotide; variolin B; vector systems, erythrocyte gene therapy; vilaresol; veratramine; verdins; verteporfin; vinorelbine; vinxaltine; integrin antagonists (vitaxin); vorozole; zanoteron; zonisamide; subsegmental vitamin C and statins.

[0142] Additional therapeutic agents that can be administered in conjunction with the combination of a menin inhibitor and a CYP3A4 inhibitor 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, clobutrazol, etc.), an alkyl sulfonate (e.g., butanesulfonate), a nitrosourea (e.g., carmustine, lomustine, etc.), or a triazene (dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, and pentostatin).

[0143] Examples of alkylating agents include, but are not limited to, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, clobutrazol, melphalan, etc.), ethyleneamines and methylamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptomycin, etc.), or triazenes (dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, floxouridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0144] 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), Dostarlimab 10 (also known as DLS-10 and NSC-376128), Isothiomivobulin (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 (such as Altorhyrtin A and Altorhyrtin C), Spongistatin (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cimadotin Hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilone (such as Epothilone A, Epothilone B, Epothilone C (also known as Deoxyepothilone A or dEpoA), Epothilone D (also known as KOS-862, dEpoB and Deoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-Aza-Epothilone B, 21-Aminoepothilone B (also known as BMS-310705), 21-Hydroxyepothilone D (also known as Deoxyepothilone 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 InstInstitute, 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), Diferrocenylacetylacetone, T-138026 (Tularik), Monsatrol, lnanocine (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 (AstaMedica), 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) (Wyeth), D-82317 (Zentoris), D-81318 (Zenteris), SC-12983 (NCI), Sodium resveratrol phosphate, BPR-OY-007 (National Health Research Institutes) and SSR-250411 (Sanofi).

[0145] The menin inhibitor and the CYP3A4 inhibitor can be used in combination with the following: immunosuppressive agents (e.g., tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine salts, mycophenolate mofetil or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, desoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids, N-aryl anthranilic acids, oxicams, coxibs or sulfonanilides), Cox-2 specific inhibitors (such as valdecoxib, celecoxib or rofecoxib), leflunomide, aurothioglucose, aurothiomalate, aurom, sulfasalazine, hydroxychloroquine, minocycline, TNF-α binding proteins (such as infliximab, etanercept or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, β-agonists, theophylline or anticholinergic agents.

[0146] Drug composition / formulation

[0147] In certain embodiments, the pharmaceutical compositions disclosed herein include a menin inhibitor and a pharmaceutically acceptable excipient, as well as a CYP3A4 inhibitor of the pharmaceutical composition and a pharmacologically acceptable excipient. In certain embodiments, the pharmaceutical composition further disclosed herein comprises (a) a menin inhibitor and a CYP3A4 inhibitor, and (b) a pharmaceutically acceptable excipient.

[0148] 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: posaconazole, conivaptan, lopinavir, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobicistat (GS-9350); an analogue or derivative of cobicistat (GS-9350); cyclosporine; delavirdine; diazepam → 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; imatinib; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof.

[0149] In some embodiments, the CYP3A4 inhibitor is posaconazole. In some embodiments, the CYP3A4 inhibitor is cobicistat (GS-9350) or an analogue 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.

[0150] In some embodiments, the menin inhibitor is amorphous or crystalline. In some embodiments, the menin inhibitor is ground or is a nanoparticle. In some embodiments, the pharmaceutical composition is a combination dosage form. In some embodiments, the composition increases the oral bioavailability of the menin inhibitor. In some embodiments, the composition increases the C max . In some embodiments, the composition increases the AUC of the menin inhibitor. In some embodiments, the composition increases the C max for the C of the menin inhibitor administered without a CYP3A4 inhibitor maxfrom about 20X to about 40X, or about 25X to about 35X. In some embodiments, the composition increases the AUC of the menin inhibitor to about 15X to about 35X, or about 20X to about 30X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition increases the AUC of the menin inhibitor to about 2X to about 35X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition increases the AUC of the menin inhibitor to about 2X to about 30X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of a CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 25X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of a CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 20X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of a CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 15X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of a CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 10X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of a CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 5X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of a CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 4X the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, compared to T max and T 1 / 2 administered without the CYP3A4 inhibitor, the composition does not significantly affect the T max and T 1 / 2 .

[0151] In some embodiments, the pharmaceutical composition further comprises chloropyrimidine, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibrutinib, tositumomab, bortezomib, pentostatin, endostatin or a combination thereof. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, daunorubicin, 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.

[0152] The pharmaceutical composition 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 pharmaceutically usable preparations. Suitable formulations depend on the chosen route of administration. Any known techniques, carriers and excipients can be used appropriately and understood in the art. An overview of the pharmaceutical compositions described herein can be found, for example, in 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 hereby incorporated by reference in their entirety.

[0153] As used herein, a pharmaceutical composition 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, dispersants, suspending agents, thickening agents, and / or excipients.

[0154] In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound disclosed herein is administered to a subject 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.

[0155] As used herein, the term "combination" refers to a product produced by the mixing or combining of a menin inhibitor and a CYP3A4 inhibitor (and any additional therapeutic agent), and includes fixed and non-fixed combinations. The term "fixed combination" refers to the administration of a menin inhibitor and a CYP3A4 inhibitor in a single entity or dosage form. The term "non-fixed combination" refers to the administration of a menin inhibitor and a CYP3A4 inhibitor as multiple separate entities or dosage forms simultaneously, concurrently, or sequentially, without a specific time interval limitation, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0156] Pharmaceutical compositions comprising the compounds described herein can be manufactured in a conventional manner, for example, by way of illustration only, by conventional mixing, dissolving, granulating, tablet-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0157] Dosage Forms

[0158] In certain embodiments, one or more dosage forms or pharmaceutical compositions are disclosed herein that comprise a menin inhibitor administered in combination with one or more dosage forms or pharmaceutical compositions comprising a CYP3A4 inhibitor.

[0159] The pharmaceutical compositions of the present application comprise a therapeutically effective amount of a compound of the present application (e.g., a menin inhibitor, a CYP3A4 inhibitor, or both) formulated together with one or more pharmaceutically acceptable carriers. The compounds of the present application can be administered as a pharmaceutical composition by any conventional route, particularly enterally, e.g., orally, such as in the form of tablets or capsules, or parenterally, such as in the form of an injectable solution or suspension, or topically, such as in the form of a lotion, gel, ointment, or cream, or in the form of a nasal or rectal suppository.

[0160] The pharmaceutical compositions can be prepared in a conventional manner by mixing, granulating or coating methods, and the pharmaceutical compositions include the individual compounds of the combination of the present application in free form or in the form of pharmaceutically acceptable salts associated with at least one pharmaceutically acceptable carrier or diluent. For example, an oral composition can be a tablet or a gelatin capsule, which contains the active ingredient and a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, there is also c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary, d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or e) absorbents, coloring agents, flavoring agents and sweetening agents. Injectable compositions can be isotonic aqueous solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifying agents, solubilizing agents, salts for regulating osmotic pressure and / or buffering agents. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal application include an effective amount of the compound of the present invention and a carrier. The carrier can include an absorbable pharmaceutically acceptable solvent to assist in passing through the skin of the host. For example, a transdermal device can be in the form of a bandage, including a backing member, a reservoir containing the compound optionally with a carrier, a rate control barrier that optionally delivers the compound to the skin of the host at a controlled and predetermined rate over a long period of time, and a device for securing the device to the skin.

[0161] Matrix transdermal formulations can also be used. Suitable formulations for topical application (e.g., to the skin and eyes) are preferably aqueous solutions, ointments, creams or gels known in the art. Such formulations may 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" refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering 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, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene 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; tragacanth powder; 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; diols, 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; ethanol and phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

[0162] The pharmaceutical compositions of the present application can be administered orally, rectally, parenterally, intracerebroventricularly, intravaginally, intraperitoneally, topically (e.g., by powder, ointment or drops), buccally or as an oral or nasal spray to humans and other animals.

[0163] As used herein, the term "pharmaceutically acceptable carrier" refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can be used 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 silicon dioxide, 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 its derivatives such as sodium carboxymethyl cellulose. Cellulose and cellulose acetate; astragalus powder; 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; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions, and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants, according to the judgment of the formulator, may also be present in the composition.

[0164] The pharmaceutical compositions of the present application can be administered to humans and other animals orally, rectally, parenterally, intracerebroventricularly, intravaginally, intraperitoneally, topically (such as by powders, ointments or drops), buccally or as an oral or nasal spray.

[0165] carrier.

[0166] Orally administered liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitol and mixtures thereof. In addition to the inert diluent, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and spices.

[0167] Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as a solvent or suspending medium. For this purpose, any mild fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0168] To prolong the effect of a drug, it is often necessary to slow the absorption of the drug following subcutaneous or intramuscular injection. This may be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn depends upon crystal size and form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

[0169] In some embodiments, a dosage form comprising a menin inhibitor and a CYP3A4 inhibitor is further disclosed herein. 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, pill or 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 combination immediate release and controlled release formulation. In some embodiments, the dosage form comprises a controlled release coating. In some embodiments, the dosage form comprises a first controlled release coating that controls the release of the menin inhibitor and a second controlled release coating that controls the release of the CYP3A4 inhibitor.

[0170] Compositions for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing the compounds of the present application with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax, which is solid at ambient temperature but liquid at body temperature and will thus melt in the rectal or vaginal cavity and release the active compound.

[0171] Solid compositions of a similar type may also be employed as fillers in hard or soft gelatin capsules, using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0172] The active compound can also be in the form of microcapsules with one or more excipients, as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well-known in the art of pharmaceutical formulations. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms can also include, as is conventional, additional substances in addition to the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also include buffering agents.

[0173] Dosage forms for topical or transdermal administration of the compounds of the present application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffering agents that may be required. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also contemplated within the scope of the present application.

[0174] In addition to the active compounds of the present application, ointments, pastes, creams, and gels can also contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0175] In addition to the compounds of the present application, powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorocarbons.

[0176] Transdermal patches have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0177] 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; cobicistat (GS-9350); an analogue 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; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; star fruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; troleandromycin, verapamil; telaprevir; vincristine; voriconazole; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is cobicistat (GS-9350) or an analogue or derivative of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0178] 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 C max In some embodiments, the dosage form increases the AUC of the menin inhibitor. In some embodiments, the dosage form increases the C max For C of the menin inhibitor administered without a CYP3A4 inhibitor maxfrom about 20X to about 40X, or from about 25X to about 35X. In some embodiments, the dosage form 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 a CYP3A4 inhibitor. In some embodiments, the dosage form increases the AUC of the menin inhibitor to about 2X to about 35X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the dosage form increases the AUC of the menin inhibitor to about 2X to about 30X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor to about 2X to about 25X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor to about 2X to about 20X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor to about 2X to about 15X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor to about 2X to about 10X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor to about 2X to about 5X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor to about 2X to about 4X of the AUC of the menin inhibitor administered without a CYP3A4 inhibitor. In some embodiments, compared to T max and T 1 / 2 administered without a CYP3A4 inhibitor, the dosage form does not significantly affect the T max and T 1 / 2。In some embodiments, the dosage form further comprises chloropyrimidine, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibrutinib, 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.

[0179] 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 requires the permission (continuous or otherwise) of a medical professional.

[0180] The pharmaceutical compositions described herein are formulated into any suitable dosage form, including but not limited to solid oral dosage forms, controlled release formulations, rapid melt formulations, effervescent formulations, tablets, powders, pills, capsules, slow release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and mixed immediate release and controlled release formulations.

[0181] Conventional pharmacological techniques include, for example, a combination of one or more of the following methods: (1) dry blending, (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, disk coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spray, tableting, extrusion, etc.

[0182] The pharmaceutical dosage forms described herein may include one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combinations thereof. In other aspects, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the pharmaceutical composition. The amount of the active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate, or isomer thereof) in a unit dose of the composition is an effective amount and varies depending on the particular treatment involved. Those skilled in the art will recognize that conventional changes in the dosage may be required from time to time depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhaled, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present application include powders, sprays, ointments, pastes, creams, emulsions, gels, solutions, patches, and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0183] The pharmaceutical compositions containing the active compounds of the present application can be manufactured in a generally known manner, such as by conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping, or lyophilization methods. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, which comprise excipients and / or auxiliaries that facilitate processing of the active compound into a pharmaceutically usable preparation. Of course, the appropriate formulation depends on the chosen route of administration.

[0184] Techniques for formulating and administering the compounds disclosed in the present application can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are combined with a pharmaceutically acceptable carrier or diluent for use in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

[0185] Administration and treatment regimens

[0186] In some embodiments, the amount of menin inhibitor administered in combination with a CYP3A4 inhibitor is from 50 mg / day up to and including 1000 mg / day.

[0187] In some embodiments, the daily dose of the menin inhibitor is between about 10 mg and 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.

[0188] In some embodiments, the dose is administered once daily, twice daily, three times daily, four times daily to equal the daily dose. In some embodiments, the menin inhibitor is administered in unit doses of 113 mg. In some embodiments, the unit dose is administered once daily, twice daily, three times daily, four times daily. In some embodiments, one unit dose is administered daily, two unit doses are administered daily, three unit doses are administered daily, four unit doses are administered daily. In some embodiments, two unit doses are administered twice daily.

[0189] In some embodiments, the amount of menin inhibitor administered is about 40 mg per day. In some embodiments, the amount of menin inhibitor administered is about 50 mg per day. In some embodiments, the amount of menin inhibitor administered is about 60 mg per day. In some embodiments, the amount of menin inhibitor administered is about 70 mg per day. In some embodiments, the amount of menin inhibitor administered is about 80 mg per day. In some embodiments, the amount of menin inhibitor administered is about 90 mg per day. In some embodiments, the amount of menin inhibitor administered is about 100 mg per day. In some embodiments, the amount of menin inhibitor administered is about 110 mg per day. In some embodiments, the amount of menin inhibitor administered is about 120 mg per day. In some embodiments, the amount of menin inhibitor administered is about 130 mg per day. In some embodiments, the amount of menin inhibitor administered is about 140 mg per day. In some embodiments, the amount of menin inhibitor administered is about 150 mg per day. In some embodiments, the amount of menin inhibitor administered is about 160 mg per day. In some embodiments, the amount of menin inhibitor administered is about 170 mg per day. In some embodiments, the amount of menin inhibitor administered is about 180 mg per day. In some embodiments, the amount of menin inhibitor administered is about 190 mg per day. In some embodiments, the amount of menin inhibitor administered is about 200 mg per day. In some embodiments, the amount of menin inhibitor administered is about 210 mg per day. In some embodiments, the amount of menin inhibitor administered is about 220 mg per day. In some embodiments, the amount of menin inhibitor administered is about 230 mg per day. In some embodiments, the amount of menin inhibitor administered is about 240 mg per day. In some embodiments, the amount of menin inhibitor administered is about 250 mg per day. In some embodiments, the amount of menin inhibitor administered is about 260 mg per day. In some embodiments, the amount of menin inhibitor administered is about 270 mg per day. In some embodiments, the amount of menin inhibitor administered is about 280 mg per day. In some embodiments, the amount of menin inhibitor administered is about 290 mg per day. In some embodiments, the amount of menin inhibitor administered is about 300 mg per day. In some embodiments, the amount of menin inhibitor administered is about 310 mg per day. In some embodiments, the amount of menin inhibitor administered is about 320 mg per day. In some embodiments, the amount of menin inhibitor administered is about 330 mg per day. In some embodiments, the amount of menin inhibitor administered is about 340 mg per 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 is given once a day, twice a day, three times a day, or four times a day. In some embodiments, the menin inhibitor is administered once a day, twice a day, or 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.

[0190] 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.

[0191] In some embodiments, the daily dose of the CYP3A4 inhibitor administered in combination with the menin inhibitor is from 50 mg / day up to and including 1000 mg / day. In some embodiments, each dose is administered once daily, twice daily, three times daily, or four times daily. 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 labeling for other indications. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 40 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 50 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 60 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 70 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 80 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 90 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 100 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 110 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 120 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 130 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 140 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 150 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 160 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 170 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 180 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 190 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 200 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 210 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 220 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 230 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 240 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 250 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 260 mg / day. In some embodiments, the amount of the CYP3A4 inhibitor administered is about 270 mg / day. In some embodiments, the amount of the 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 daily, twice daily, three times daily, or four times daily.

[0192] In some embodiments, the AUC of the menin inhibitor co-administered with the CYP3A4 inhibitor 0-24 is between about 50 and about 10000 ng*h / mL. In some embodiments, the C of the menin inhibitor co-administered with the CYP3A4 inhibitor max is between about 5 ng / mL and about 1000 ng / mL. [[ID=⑧]] [[ID=⑨]]

[0193] 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, which is 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, which is 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 as a 300 mg injection once daily. In some embodiments, the CYP3A4 inhibitor is posaconazole, which is administered as a 300 mg injection twice daily, then once daily. In some embodiments, the CYP3A4 inhibitor is posaconazole, and posaconazole is administered as a 300 mg tablet once daily. 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, divided into two 400 mg administrations twice daily.

[0194] 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 daily. In some embodiments, ritonavir is administered at 300 mg twice daily, and increased by 100 mg twice daily at intervals of 2 to 3 days.

[0195] 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 daily.

[0196] 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, or 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 therapies. In some embodiments, the menin inhibitor is a maintenance therapy.

[0197] In some embodiments, the compositions disclosed herein are used for prophylaxis, treatment, or maintenance treatment. In some embodiments, the compositions disclosed herein are for therapeutic use. In some embodiments, the compositions disclosed herein are administered as a maintenance therapy, e.g., for patients in remission.

[0198] In the event that the patient's condition does not improve, the compound can be administered continuously; alternatively, the dose of the administered drug can be increased over a period of time. The increase in the length of the drug administration can vary between 2 days and 1 year, by way of example only, including 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 dose increase can be 10% - 200%, by way of example only, including 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%.

[0199] If the patient's condition does not improve, the dose or frequency of administration, or both, can be increased according to the symptoms to a level that improves the disease, disorder, or condition.

[0200] If the patient's condition does improve, the dosage of the administered drug can be temporarily reduced or 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 and, by way of example only, includes 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 from 10% - 100% and, by way of example only, includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0201] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, the dosage or frequency of administration, or both, can be adjusted according to symptoms to maintain the improved level of the disease, disorder, or condition. However, once the symptoms recur, the patient may require long-term intermittent treatment.

[0202] The amount of a given reagent corresponding to this quantity will vary depending on factors such as the specific compound, the severity of the disease, the identity of the subject or host to be treated (e.g., body weight), etc., but can still be routinely determined in a manner known in the art according to the specific circumstances surrounding the case, including, for example, the specific reagent administered, the route of administration, and the subject or host being treated. However, generally speaking, the dosage for adult treatment is usually 0.02 - 5000 mg / day, or approximately 1 - 1500 mg / day. The required dosage can be conveniently administered as a single dose or divided doses simultaneously (or within a short period of time) or at appropriate intervals (e.g., twice, three times, four times, or more sub-doses per day).

[0203] The pharmaceutical compositions described herein can be unit dosage forms suitable for single administration in precise dosages. In a unit dosage form, the preparation is divided into unit doses containing an appropriate amount of one or more compounds. The unit dosage form can be a packaged form containing discrete amounts of the preparation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-resealable containers.

[0204] Alternatively, multi-dose resealable containers can be used, in which case a preservative is usually included in the composition. By way of example only, preparations for parenteral injection can be presented in unit dosage form, including but not limited to ampoules or multi-dose containers, with a preservative added.

[0205] The above ranges are merely illustrative because the number of variables related to an individual treatment regimen is large, and significant deviations from these recommended values are not uncommon. Such dosage can be varied according to a variety of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition to be treated, and the judgment of the physician.

[0206] The toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to LD 50 (the dose lethal to 50% of the population) and ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio between LD 50 and ED 50 . Compounds showing a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a range of doses for use in humans. The doses of such compounds are preferably within the range of circulating concentrations, including the ED 50 with the least toxicity. The dose can vary within this range depending on the dosage form used and the route of administration employed.

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

[0208] In some embodiments, a menin inhibitor and a CYP3A4 inhibitor are administered in parallel. In some embodiments, a menin inhibitor and a CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen. In some embodiments, a menin inhibitor and a CYP3A4 inhibitor are administered sequentially.

[0209] Kit / Manufactured article

[0210] For use in the treatment methods described herein, kits and manufactured articles are also described herein. Such a kit includes a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials, tubes, etc., each container including 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 container is formed of a variety of materials such as glass or plastic.

[0211] The manufactured articles provided herein include packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, vials, and any packaging material suitable for a selected formulation and mode of administration and treatment.

[0212] For example, the container includes a CYP3A4 inhibitor, optionally in the form of a composition or in combination with a CYP3A4 inhibitor disclosed herein. Such kits optionally include an identifying description or label or instructions related to its use in the methods described herein.

[0213] The kit generally includes a label listing the contents and / or instructions for use, as well as a package insert with instructions for use. A set of instructions will also typically be included.

[0214] In some embodiments, the label is on the container or associated with the container. In some embodiments, the label is on the container when the letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself; the label is associated with the container when the label is present within a receptacle or carrier that also holds the container, such as a package insert. In some embodiments, the label is used to indicate that the contents are for a specific therapeutic application. The label also indicates the instructions for use of the contents, such as in the methods described herein.

[0215] In certain embodiments, the pharmaceutical composition is presented in a packaging or dispenser device containing one or more unit dosage forms containing the compounds provided herein. For example, the packaging includes a metal or plastic foil, such as a blister pack. In some embodiments, the packaging or dispenser device is accompanied by instructions for administration. In some embodiments, the packaging or dispenser is also attached with a notice associated with the container, the form of which is specified by a government agency that regulates the manufacture, use, or sale of the drug, and the notice reflects the agency's approval of the form of the drug for human or veterinary administration. For example, such a notice is a prescription drug label approved by the U.S. Food and Drug Administration, or an approved product insert. In some embodiments, a composition containing the compounds provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0216]

[0217]

[0218] Examples

[0219] The following ingredients, formulations, processes, and procedures for practicing the methods disclosed herein correspond to the above and are not meant to limit the above embodiments.

[0220] Example 1: Treatment with a menin inhibitor of Formula I or Formula II alone and in combination with a CYP3A4 inhibitor

[0221] Patients with R / R acute leukemia aged ≥ 12 years with no available therapy were enrolled. The menin inhibitor was administered on a q12h schedule; alternative dosing schedules were considered. The menin inhibitor was administered orally (PO) in 28-day cycles, with the first dose administered on Cycle 1 Day 1 (C1D1). Patients continued treatment until progressive disease (PD) or unacceptable toxicity.

[0222] Patients were assigned to one of two groups as described below:

[0223] · Group A: Patients were not to receive any strong cytochrome P450 3A4 (CYP3A4) inhibitor / inducer. Patients receiving a strong CYP3A4 inhibitor / inducer had to discontinue the medication at least 7 days prior to enrollment.

[0224] · Group B: Patients had to receive itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis and concurrent treatment for at least 7 days prior to enrollment. Patients were not to receive any other strong CYP3A4 inhibitor / inducer.

[0225] The dose of the menin inhibitor was determined in patients with acute leukemia. The mutation status was unknown at the time of enrollment of patients with R / R acute leukemia. The exact dose intensity was rounded to accommodate capsule size limitations (113 mg / capsule). The starting dose was 113 mg q12h and was increased to higher doses or decreased to lower doses as shown in the table below.

[0226] Dose levels of the menin inhibitor

[0227]

[0228]

[0229] The efficacy of the menin inhibitor and combination therapy was explored in 3 indication-specific cohorts as follows:

[0230] · Cohort 2A: MLLr ALL / MPAL patients.

[0231] · Cohort 2B: MLLr AML patients.

[0232] · Cohort 2C: NPM1c AML patients.

[0233] Each cohort used a Simon 2-stage design with up to 34 patients per cohort. Enrollment for each expansion cohort was conducted independently. For patients with R / R acute leukemia carrying NPM1c or MLL gene rearrangements and with no available treatment options, a CR+CRh rate > 15% was considered the lower limit of anti-leukemic activity.

[0234] The anti-tumor activity of the menin inhibitor was evaluated in genetically defined cohorts. These patient subsets had leukemias expressing the targets against which the menin inhibitor was expected to be most effective.

[0235] Doses were based on data generated from 28-day GLP toxicology studies in rats and dogs. 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 dog HNSTD (50 mg / kg; 1000 mg / m 2 ) was lower than the rat STD10 (400 mg / kg; 2400 mg / m 2 ); thus, the clinical starting dose for dogs was 1 / 6 HNSTD or 166.7 mg / m 2 , 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 as 113 mg PO q12h.

[0236] The safety, tolerability, MTD, and RP2D of the menin inhibitor and combination therapy were determined in patients with R / R acute leukemia in Groups A and B, respectively. The PK parameters of the menin inhibitor and combination therapy were determined in Groups 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.

[0237] Determine secondary objectives:

[0238] · Composite CR (CRc) rate (CR+CRh+CR with incomplete hematologic recovery [CRi]+CR with incomplete platelet recovery [CRp]).

[0239] · CR rate at 4 weeks of treatment.

[0240] · Best overall response rate (BORR) (CRc + partial response [PR]).

[0241] · Relapse-free survival rate (RFS).

[0242] · Time to response (TTR) and duration of response (DOR)

[0243] · Overall survival rate (OS).

[0244] · 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 。

[0245] The anti-leukemia activities of the menin inhibitors and combinations of the present invention were determined. The pharmacodynamic, safety and efficacy relationships of the menin inhibitors and combinations of the present invention with relevant biomarkers may include immunophenotype, gene expression, mutation analysis and minimal residual disease (MRD) of circulating peripheral blood mononuclear cells (PBMC) and / or bone marrow.

[0246] Recorded R / R acute leukemia.

[0247] Group A: Patients must not receive any strong cytochrome P450 3A4 (CYP3A4) inhibitor / inducer. Patients receiving strong CYP3A4 inhibitor / inducer must discontinue the medication at least 7 days before enrollment.

[0248] Group B: Patients must receive itraconazole, ketoconazole, posaconazole or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis for at least 7 days before enrollment, while receiving treatment with menin inhibitors. Patients must not receive any other strong CYP3A4 inhibitor / inducer.

[0249] Group 2A: Recorded R / R ALL / MPAL with MLLr translocation.

[0250] Group 2B: Recorded R / R AML with MLLr translocation.

[0251] Group 2C: Recorded R / R AML with NPM1c.

[0252] 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 with unconfirmed mutation status were replaced.

[0253] Relapsed or refractory AML / ALL or MPAL as defined by standardized criteria after standard-of-care therapy (such as European LeukemiaNet criteria; International Working Group criteria). Patients with persistent leukemia after initial therapy, or who relapse at any time during or after treatment (including allogeneic hematopoietic stem cell transplantation [HSCT]) after a response are eligible.

[0254] Prior therapy:

[0255] Any prior treatment-related toxicities had resolved to ≤ grade 1 prior to enrollment, except for ≤ grade 2 neuropathy or alopecia.

[0256] Radiation therapy : At least 60 days since prior total body irradiation (TBI), craniospinal irradiation, and / or ≥ 50% pelvic irradiation, or at least 14 days since local palliative irradiation therapy (small port).

[0257] Stem cell infusion : At least 60 days must have elapsed since HSCT, at least 4 weeks (starting from the first dose) must have elapsed since donor lymphocyte infusion (DLI), and there is no conditioning.

[0258] Immunotherapy : At least 42 days since prior immunotherapy (including tumor vaccines and checkpoint inhibitors), and at least 21 days since receiving chimeric antigen receptor therapy or other modified T cell therapies.

[0259] Anti-leukemia therapy : At least 14 days since completion of anti-leukemia therapy (such as, but not limited to, small molecule or cytotoxic / myelosuppressive therapy), with the following exceptions: With medical supervision approval, cytoreduction with hydroxyurea can be initiated and continued with menin inhibitor. Intrathecal chemotherapy at the time of diagnostic lumbar puncture, at least 24 hours prior to starting menin inhibitor. Patients are allowed to receive intrathecal chemotherapy.

[0260] Hematopoietic growth factor : At least 7 days since completion of short-acting hematopoietic growth factor therapy, and 14 days for long-acting growth factor therapy.

[0261] Biological agents (such as monoclonal antibody therapy) : At least 7 days or 5 half-lives, whichever is longer, since completion of therapy with a biologic reagent.

[0262] Steroids : At least 7 days since systemic glucocorticoid therapy, unless receiving physiological dosing (equivalent to ≤ 10 mg prednisone per day) or cytoreduction therapy. Cytoreduction therapy must be approved by the medical monitor.

[0263] Menin inhibitor administration

[0264] Based on the patient cohort assignment, take menin inhibitor capsules (113 mg and 156 mg free base equivalents) at the specified dose q12h for PO administration. The menin inhibitor is administered on an empty stomach, at least 2 hours after a meal and 1 hour before the next meal.

[0265] All patients receive the menin inhibitor PO q12h over a 28-day cycle, with the first study drug dose administered on C1D1. Alternative dosing regimens may be made according to the dosing schedule above. Patients continue dosing until PD or unacceptable toxicity occurs.

[0266] Dose assignment: Phase 1

[0267] The starting dose of the menin inhibitor is 113 mg q12h (226 mg total daily dose). The dosing of the menin inhibitor increases with the CYP3A4 dose.

[0268] The doses for Groups A and B that meet the following criteria are determined independently:

[0269] · ≤ 1 / 6 of the DLT evaluable patients experience DLT.

[0270] · At least two-thirds of the patients receive at least 80% of their prescribed dose in C1 and C2, unless due to PD.

[0271] · At least 3 patients are evaluable for PK.

[0272] · The area under the plasma concentration curve value (AUC0-24) of at least two-thirds of the patients is ≥ 15,000 ng hr / mL from 0 to 24 hours.

[0273] - If the MTD does not reach this exposure level but efficacy is seen at any dose level, the highest dose level that meets the above safety and tolerability criteria will be selected as the RP2D

[0274] If the highest tested dose does not meet all 4 RP2D criteria, the next lower dose level will be expanded to a total of 6 patients. The expansion of the lower dose levels will continue in a sequential manner until a dose that meets the RP2D criteria is determined. In addition, observations related to PK and any cumulative toxicity observed after multiple cycles may be included in the rationale supporting the RP2D.

[0275] If a 100% CR rate is observed at the end of Cycle 1 and the dose level is safe and tolerable within the 3 + 3 dose escalation period, that dose will be defined as the RP2D.

[0276] Efficacy

[0277] Conduct disease assessment and evaluate disease response.

[0278] · Complete remission (CR): Blast cells in bone marrow < 5%; no circulating blast and Auer rod blast; no extramedullary disease; ANC ≥ 1.0 × 10 9 / L (1000 / μL) and platelet count ≥ 100 × 10 9 / L (100000 / μL)

[0279] · CR with partial hematological recovery (CRh): Blast cells in bone marrow < 5%; no circulating blast and Auer rod blast; no extramedullary disease; residual neutropenia (> 0.5 × 10 9 / L [1000 / μL]) and thrombocytopenia (> 50 × 10 9 / L [100000 / μL])

[0280] · CR with incomplete hematological recovery (CRi): Blast cells in bone marrow < 5%; no circulating blast and Auer rod blast; no extramedullary disease; residual neutropenia (< 1.0 × 10 9 / L [1000 / μL]) or thrombocytopenia (< 100 × 10 9 / L [100000 / μL])

[0281] · CR with incomplete platelet recovery (CRp): Blast cells in bone marrow < 5%; no circulating blast and Auer rod blast; no extramedullary disease; ANC ≥ 1.0 × 10 9 / L (1000 / μL) and platelet count < 100 × 10 9 / L (100000 / μL).

[0282] · Partial remission (PR): Percentage of blast cells in bone marrow reduced to 5% - 25%; percentage of blast cells in pre-treatment bone marrow reduced by at least 50%; ANC ≥ 1.0 × 10 9 / L (1000 / μL) and platelet count ≥ 100 × 10 9 / L (100000 / μL).

[0283] Pharmacokinetics

[0284] Blood samples of approximately 5 mL each will be collected to measure the plasma concentration of the menin inhibitor. Up to 24 additional samples may be collected at other time points during the study.

[0285] Blood samples for PK were collected at C1D1, C1D8, C3D1 and C5D1 before dosing (within 1 hour before dosing) and at 0.25, 0.5 and 1 hour (±5 minutes), 2 and 4 hours (±15 minutes), and 8 hours (±30 minutes) after dosing, and centrifuged to prepare plasma. For Group B only, PK samples should also be collected at C1D3 or 4 before dosing (within 1 hour before dosing). On the PK sample collection day, the menin inhibitor was taken at the research center under the observation of the research center staff.

[0286] Statistical considerations

[0287] Statistical hypotheses

[0288] This study adopted the Simon minimax 2-stage design. It was assumed that the true CR+CRh rate was 35%. In patients with relapsed and refractory acute leukemia, a CR+CRh rate >15% was considered the lower limit of anti-leukemia activity.

[0289] Twenty-one patients were enrolled in each cohort. If 4 or more patients in a single cohort responded, then an additional 13 patients would be enrolled in that cohort. If 10 or more CR+CRh patients were observed among the 34 patients in the cohort, then the treatment was worthy of further evaluation.

[0290] Sample size determination

[0291] The actual number of patients enrolled in the first stage depended on the dose level at which toxicity occurred and the number of dose levels investigated to determine the MTD and RP2D. It was expected that up to 54 patients would be enrolled in the first stage, up to 30 patients in Group A, and up to 24 patients in Group B. No formal sample size calculation was performed in the first stage of the study.

[0292] The number of patients in each cohort evaluated in each stage and the minimum number of responders required to proceed to the next stage were determined based on the minimax version of Simon's 2-stage design, with 80% power and a one-sided significance level of 2.5%. Up to 34 patients were enrolled in each cohort. It was assumed that the true CR+CRh rate was 35%. A CR+CRh rate greater than 15% was considered the lower threshold of anti-leukemia activity. According to the design elements defined above, in the first stage, up to 21 patients would be enrolled in each cohort: if 4 or more patients achieved CR+CRh, then 13 patients would be enrolled in the second stage. Otherwise, enrollment in that cohort would be terminated. After completion of the second stage, if 10 or more patients among the 34 enrolled patients in the cohort achieved CR+CRh, then this patient population could be further evaluated. If the true CR+CRh rate of the leukemia subtype was 15% or lower, the probability of terminating enrollment at the end of the first stage was 61%.

[0293] Therefore, it is anticipated that up to 156 patients will be enrolled in this study and treated with a combination of a menin inhibitor of Formula I or Formula II and a CYP3A4 inhibitor.

[0294] Analysis

[0295] For the purpose of analysis, the following populations were defined:

[0296]

[0297] Statistical Analysis

[0298] The detailed methods for the aggregation 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 populations included in the analysis, as well as the procedures used to account for missing, unused, and spurious data. This section summarizes the planned statistical analysis for the primary and secondary endpoints. Statistical analysis of exploratory endpoints. Time-to-event data will be analyzed using the Kaplan-Meier method and the results will be summarized at the 25th, 50th (median), and 75th percentiles, with associated two-sided 95% CIs, as well as the percentage of censored observations.

[0299] Using version or later (SAS Institute Inc, Cary NC) for statistical analysis. Programming specifications describing the data sets and variables created for this study will be prepared. Data sets will be prepared using the most recent version of the CDISC Study Data Tabulation Model (SDTM) and Analysis Data Set Model (ADaM).

[0300] Pharmacokinetic Analysis

[0301] Plasma concentrations of the administered menin inhibitor will be determined using a validated bioanalytical assay. The following PK parameters will be calculated from plasma concentrations measured at C1D1, C1D8, C3D1, and C5D1 (if applicable): C max 、T max 、AUC 0-t 、AUC 0-24 、CL / F, Vz / F, and t 1 / 2 , by conventional non-compartmental analysis when sufficient data are available. Concentrations at 12 h post-dose in the morning (for pre-dose of evening dosing) will be estimated using concentrations in samples collected pre-dose in the morning (for pre-dose of morning dosing) as these values should be similar. AUC 0-24 at steady state can be calculated as twice the AUC 0-12 for q12h dosing.

[0302] Summary statistics for plasma concentrations and pharmacokinetic parameters will be generated by dose cohort and across cohorts.

[0303] Other Analyses

[0304] The pharmacodynamic and biomarker exploratory analyses will be described in the statistical analysis plan to be completed before database lock.

[0305] Strong inhibitors and inducers of CYP3A4 and CYP3A substrates with a narrow therapeutic range

[0306]

[0307] Abbreviations: AUC area under the concentration-time curve; CYP3A4 cytochrome P450 3A4.

[0308] a Increase the AUC of the substrate by ≥5-fold

[0309] b Decrease the AUC of the substrate by ≥80%

[0310] c Drugs for which the exposure-response relationship indicates that a small increase in exposure level with concomitant use of a CYP inhibitor may lead to serious safety issues (e.g., torsades de pointes)

[0311] Note: The above list is not exhaustive. See also:

[0312] http: / / www.fda.gov / drugs / developmentapprovalprocess / developmentresources / druginteractionslabeling / ucm093664.htm

[0313] Equivalents

[0314] The examples and embodiments described herein are illustrative and modifications or changes suggested to those skilled in the art will be included in this disclosure. As will be understood by those skilled in the art, the specific components listed in the above examples may be replaced with other functionally equivalent components, such as diluents, binders, lubricants, fillers, etc.

Claims

1. A method for treating an individual in need thereof, comprising administering a combination of a menin inhibitor and a CYP3A4 inhibitor.

2. A method for treating an individual in need thereof, comprising administering a pharmaceutical composition comprising a menin inhibitor and a pharmaceutical composition comprising a CYP3A4 inhibitor.

3. The method of any one of the preceding claims, wherein the menin inhibitor is selected from formula (I) and formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, geometric isomer or tautomer thereof.

4. The method of any one of the preceding claims, wherein the menin inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, geometric isomer or tautomer thereof.

5. The method of any one of the preceding claims, wherein the menin inhibitor is an inhibitor, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, geometric isomer or tautomer thereof.

6. The method of any one of the preceding claims, wherein the CYP3A4 inhibitor is selected from the group consisting of: boceprevir, nefazodone, clarithromycin, nelfinavir, conivaptan, posaconazole, grapefruit juice, ritonavir, indinavir, saquinavir, itraconazole, telaprevir, ketoconazole, telithromycin, lopinavir, voriconazole, cobicistat, mibefradil.

7. The method of any one of the preceding claims, wherein the CYP3A4 is an azole antifungal agent.

8. The method of any one of the preceding claims, wherein the CYP3A4 inhibitor is posaconazole.

9. The method of any one of the preceding claims, wherein the CYP3A4 inhibitor is cobicistat.

10. The method of any one of the preceding claims, wherein the CYP3A4 inhibitor is ketoconazole.

11. The method of any one of the preceding claims, wherein the CYP3A4 inhibitor is ritonavir.

12. The method of any one of the preceding claims, wherein the menin inhibitor and the CYP3A4 inhibitor are in a combined dosage form.

13. The method of any one of claims 1-11, wherein the menin inhibitor and the CYP3A4 inhibitor are in separate dosage forms.

14. The method of any one of the preceding claims, wherein the menin inhibitor is administered in a sub-therapeutically effective amount.

15. The method of any one of the preceding claims, wherein the CYP3A4 inhibitor is administered in a therapeutically effective amount.

16. The method of any one of claims 1-14, wherein the CYP3A4 inhibitor is administered in a sub-therapeutically effective amount.

17. The method of any one of the preceding claims, wherein the menin inhibitor and the CYP3A4 inhibitor are administered simultaneously.

18. The method of any one of the preceding claims, wherein the menin inhibitor and the CYP3A4 inhibitor are administered simultaneously, substantially simultaneously or within the same treatment regimen.

19. The method of any one of the preceding claims, wherein the menin inhibitor and the CYP3A4 inhibitor are administered sequentially.

20. The method of any one of the preceding claims, wherein the combination is administered for an initial treatment period, followed by continued administration of the menin inhibitor.

21. The method of any one of the preceding claims, wherein the administration of the CYP3A4 inhibitor occurs before the administration of the menin inhibitor.

22. A kit for treating cancer in an individual, comprising a combination of a menin inhibitor and a CYP3A4 inhibitor.

23. The kit of claim 22, wherein the menin inhibitor is selected from formula (I) and formula (II) or a pharmaceutically acceptable salt, stereoisomer, geometric isomer or tautomer thereof.

24. The kit of any one of claims 22-23, further comprising instructions on how to use the kit.

25. A composition of a menin inhibitor and a CYP3A4 inhibitor, wherein the menin inhibitor and the CYP3A4 inhibitor are in contact with each other in a human body (e.g., only in a human body).

26. The composition of claim 25, wherein the menin inhibitor is selected from formula (I) and formula (II) or a pharmaceutically acceptable salt, stereoisomer, geometric isomer or tautomer thereof.

27. A method of preparing a composition by bringing a menin inhibitor and a CYP3A4 inhibitor into contact with each other at a site.

28. The method of claim 27, wherein the menin inhibitor is selected from formula (I) and formula (II) or a pharmaceutically acceptable salt, stereoisomer, geometric isomer or tautomer thereof.

29. A combination of a menin inhibitor and a CYP3A4 inhibitor for use in the preparation of a medicament for treating cancer.

30. The method of any one of claims 1-21, wherein the CYP3A4 inhibitor is a strong CYP3A4 inhibitor.

31. A method of treating cancer in a patient, comprising the steps of: a) administering a pharmaceutical composition comprising posaconazole, and b) administering a pharmaceutical composition comprising a menin inhibitor of formula (II) or a pharmaceutically acceptable salt thereof 32. The method of any one of claims 1-21 or 31, wherein the menin inhibitor is fumarate.

33. The method of any one of claims 1-21 or 31-32, wherein the menin inhibitor is sesquifumarate.

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