Treatment using nilogacestat

Abstract

The present disclosure relates to an improved method for the treatment with nilogase stat. The present invention further includes an improved method for treating conditions responsive to gamma-secretase inhibition, such as desmoid tumors, multiple myeloma, ovarian granulosa cell tumors, etc., with nilogase stat and pharmaceutically acceptable salts thereof.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 365,125, filed May 20, 2022, and U.S. Provisional Application No. 63 / 365,193, filed May 23, 2022, each of which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to improved methods of treating with nirogacestat.

Background Art

[0003] (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentaamide (hereinafter referred to as "nirogacestat" or the compound of formula (I)) is a gamma-secretase inhibitor that can inhibit the production of Aβ peptide.

Chemical Formula

[0004] Desmoid tumors are rare soft tissue tumors, also known as aggressive fibromatosis, which are locally invasive and grow slowly. According to the World Health Organization (WHO), desmoid tumors are defined as clonal proliferations of fibroblasts that occur in deep soft tissues and are characterized by invasive growth and a tendency for local recurrence but do not metastasize (Kasper et al. Oncologist, 2011, 16(5):682-93). Although desmoid tumors are considered benign, they can cause serious conditions by infiltrating vital structures or exerting a mass effect (Lewis et al., Ann Surg. 1999, 229(6):866-72, Smith et al., Br J Surg. 2000, 87(5):608-13). Desmoid tumors include soft tissue masses that occur anywhere in the body in different types of connective tissue, including the attachment tissues of muscles and fascia. Desmoid tumors infiltrate surrounding structures, spread along plains and muscles, and can cause severe pain, functional impairment, and, more rarely, life-threatening conditions (Penel et al., Eur J Cancer. 2017, 83:125-31). Despite being benign, desmoid tumors act aggressively, cause significant morbidity, and have an increased local recurrence rate (reaching up to 60%) even after wide resection (Penel, 2017).

[0005] Therefore, there is currently a need for a composition comprising nilogarstat or a pharmaceutically acceptable salt thereof for treating a patient having a disease or disorder responsive to treatment with a gamma-secretase inhibitor. SUMMARY OF THE INVENTION

[0006] The present invention provides an improved method of treating conditions responsive to gamma-secretase inhibition with nilogarstat and pharmaceutically acceptable salts thereof, including, for example, desmoid tumors, multiple myeloma, ovarian granulosa cell tumors, and the like.

[0007] One embodiment is a method for treating a condition responsive to inhibition of gamma-secretase, such as desmoid tumor or multiple myeloma, in a patient in need thereof, comprising orally administering nilotinib or a pharmaceutically acceptable salt thereof to the patient twice daily at a dose of 150 mg (free base equivalent dose), and the treatment method includes one or more of the following: (a) For a patient in whom grade 3 diarrhea persists for at least 3 days despite maximal medical treatment, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the diarrhea is grade 1 or less diarrhea or has recovered to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (b) For a patient who develops grade 3 folliculitis, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the folliculitis is grade 1 or less folliculitis or has recovered to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (c) For a patient with grade 3 maculopapular rash, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the maculopapular rash is grade 1 or less maculopapular rash or has recovered to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (d) For a patient with grade 3 hidradenitis, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the hidradenitis is grade 1 or less hidradenitis or has recovered to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) once daily. (e) For patients in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, withhold nirogacestat or a pharmaceutically acceptable salt thereof until the hypophosphatemia has recovered to grade 1 or lower hypophosphatemia or to baseline, and then resume oral administration of nirogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (equivalent free base dose). (f) For patients with grade 3 hypokalemia despite maximum replacement therapy, withhold nirogacestat or a pharmaceutically acceptable salt thereof until the hypokalemia has recovered to grade 1 or lower hypokalemia or to baseline, and then resume oral administration of nirogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (equivalent free base dose), and (g) For patients with alanine transaminase (ALT) or aspartate aminotransferase (AST) at 3 to 5 times the upper limit of the reference range (ULN), withhold nirogacestat or a pharmaceutically acceptable salt thereof until ALT, AST, or both have recovered to 3 times or less, and then resume oral administration of nirogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (equivalent free base dose).

[0008] In one embodiment, the method further includes one or more of the following: (h) For patients with ALT or AST above 5 times the ULN, permanently discontinue treatment with nirogacestat or a pharmaceutically acceptable salt thereof. (i) For patients showing anaphylaxis or other severe allergic reactions, permanently discontinue treatment with nirogacestat or a pharmaceutically acceptable salt thereof, and (j) In the case of another severe adverse reaction or a life-threatening adverse reaction, until the adverse reaction is an adverse reaction of Grade 1 or lower or has recovered to the baseline, nilotinib or a pharmaceutically acceptable salt thereof shall be discontinued, and then, after carefully considering the potential benefits and the possibility of recurrence of the adverse reaction, (A) oral administration of nilotinib or a pharmaceutically acceptable salt thereof shall be resumed at a dose of 100 mg (free base equivalent dose) twice a day, and (B) if a severe or life-threatening adverse reaction recurs at a dose of 100 mg (free base equivalent dose) twice a day, treatment with nilotinib or a pharmaceutically acceptable salt thereof shall be permanently discontinued.

[0009] In another embodiment, the method includes, for a patient in whom Grade 3 diarrhea persists for at least 3 days despite maximum medical treatment, discontinuing nilotinib or a pharmaceutically acceptable salt thereof until the diarrhea is Grade 1 or lower diarrhea or has recovered to the baseline, and then resuming oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day.

[0010] In yet another embodiment, the method includes, for a patient having Grade 3 folliculitis, discontinuing nilotinib or a pharmaceutically acceptable salt thereof until the folliculitis is Grade 1 or lower folliculitis or has recovered to the baseline, and then resuming oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day.

[0011] In yet another embodiment, the method includes, for a patient having Grade 3 maculopapular rash despite maximum medical treatment, discontinuing nilotinib or a pharmaceutically acceptable salt thereof until the maculopapular rash is Grade 1 or lower maculopapular rash or has recovered to the baseline, and then resuming oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day.

[0012] In yet another embodiment, the method comprises, for a patient having a grade 3 macular papular rash, withholding nilotinib or a pharmaceutically acceptable salt thereof until the macular papular rash has recovered to a macular papular rash of grade 1 or lower or to baseline, and then restarting oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

[0013] In yet another embodiment, the method comprises, for a patient having grade 3 hypophosphatemia that persists for at least 7 days despite maximum replacement therapy, withholding nilotinib or a pharmaceutically acceptable salt thereof until the hypophosphatemia has recovered to a hypophosphatemia of grade 1 or lower or to baseline, and then restarting oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

[0014] In yet another embodiment, the method comprises, for a patient having grade 3 hypokalemia despite maximum replacement therapy, withholding nilotinib or a pharmaceutically acceptable salt thereof until the hypokalemia has recovered to a hypokalemia of grade 1 or lower or to baseline, and then restarting oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

[0015] In yet another embodiment, the method comprises, for a patient in whom ALT or AST is 3 to 5 times the ULN, withholding nilotinib or a pharmaceutically acceptable salt thereof until ALT, AST, or both have returned to 3 times the ULN or lower or to baseline, and then restarting oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

[0016] In yet another embodiment, the method comprises permanently discontinuing treatment with nilotinib or a pharmaceutically acceptable salt thereof for a patient having an ALT or AST greater than 5 times the ULN.

[0017] In yet another embodiment, the method includes (i) permanently discontinuing treatment with nilogacestat or a pharmaceutically acceptable salt thereof in a patient exhibiting anaphylaxis or other severe allergic reaction.

[0018] In yet another embodiment, the method includes: (a) For a patient in whom grade 3 diarrhea has persisted for at least 3 days despite maximal medical treatment, withholding nilogacestat or a pharmaceutically acceptable salt thereof until the diarrhea is grade 1 or less or has recovered to baseline, and then restarting oral administration of nilogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (free base equivalent dose), (b) For a patient who has developed grade 3 folliculitis, withholding nilogacestat or a pharmaceutically acceptable salt thereof until the folliculitis is grade 1 or less or has recovered to baseline, and then restarting oral administration of nilogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (free base equivalent dose), (c) For a patient with grade 3 papular-patchy rash, withholding nilogacestat or a pharmaceutically acceptable salt thereof until the papular-patchy rash is grade 1 or less or has recovered to baseline, and then restarting oral administration of nilogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (free base equivalent dose), (d) For a patient with grade 3 hidradenitis, withholding nilogacestat or a pharmaceutically acceptable salt thereof until the hidradenitis is grade 1 or less or has recovered to baseline, and then restarting oral administration of nilogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (free base equivalent dose), (e) For patients in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, withhold nilogicitat or a pharmaceutically acceptable salt thereof until the hypophosphatemia has recovered to grade 1 or lower hypophosphatemia or to baseline, and then resume oral administration of nilogicitat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (f) For patients with grade 3 hypokalemia despite maximum replacement therapy, withhold nilogicitat or a pharmaceutically acceptable salt thereof until the hypokalemia has recovered to grade 1 or lower hypokalemia or to baseline, and then resume oral administration of nilogicitat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (g) For patients with ALT or AST that is 3 to 5 times the upper limit of normal (ULN), withhold nilogicitat or a pharmaceutically acceptable salt thereof until the ALT, AST, or both have recovered to 3 times or less the ULN, and then resume oral administration of nilogicitat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

[0019] In yet another embodiment, the method includes the following: (a) For patients in whom grade 3 diarrhea persists for at least 3 days despite maximum medical treatment, withhold nilogicitat or a pharmaceutically acceptable salt thereof until the diarrhea has recovered to grade 1 or lower diarrhea or to baseline, and then resume oral administration of nilogicitat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (b) For patients who develop grade 3 folliculitis, withhold nilogicitat or a pharmaceutically acceptable salt thereof until the folliculitis has recovered to grade 1 or lower folliculitis or to baseline, and then resume oral administration of nilogicitat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (c) For patients with grade 3 macular papular rash, withhold nilotinib or a pharmaceutically acceptable salt thereof until the macular papular rash recovers to grade 1 or lower macular papular rash or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (d) For patients with grade 3 hidradenitis, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hidradenitis recovers to grade 1 or lower hidradenitis or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (e) For patients in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hypophosphatemia recovers to grade 1 or lower hypophosphatemia or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (f) For patients with grade 3 hypokalemia despite maximum replacement therapy, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hypokalemia recovers to grade 1 or lower hypokalemia or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (g) For patients with ALT or AST that is 3 to 5 times the ULN, withhold nilotinib or a pharmaceutically acceptable salt thereof until ALT, AST, or both return to 3 times the ULN or lower or to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (h) For patients with ALT or AST greater than 5 times the ULN, permanently discontinue the administration of nilotinib or a pharmaceutically acceptable salt thereof. (i) Permanently discontinue treatment with nirogacestat or a pharmaceutically acceptable salt thereof in patients with anaphylaxis or other severe hypersensitivity reactions, and (j) In the case of another severe adverse reaction or a life-threatening adverse reaction, withhold nirogacestat or a pharmaceutically acceptable salt thereof until the adverse reaction is a Grade 1 or lower adverse reaction or has recovered to baseline, and then, after carefully considering the potential benefits and the likelihood of recurrence of the adverse reaction, (A) resume oral administration of nirogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (free base equivalent dose), and (B) permanently discontinue treatment with nirogacestat or a pharmaceutically acceptable salt thereof if a severe or life-threatening adverse reaction occurs at a dose of 100 mg twice daily (free base equivalent dose).

[0020] In yet another embodiment, for patients with Grade 3 skin reactions, withhold nirogacestat or a pharmaceutically acceptable salt thereof until the skin reaction has recovered to a Grade 1 or lower skin reaction, and then resume oral administration of nirogacestat or a pharmaceutically acceptable salt thereof at a dose of 100 mg twice daily (free base equivalent dose).

[0021] In yet another embodiment of any of the methods described herein, the patient has a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene.

[0022] In yet another embodiment of any of the methods described herein, the patient has a mutation in the CTNNB1 (β-catenin) gene.

[0023] In yet another embodiment of any of the methods described herein, the patient has been previously treated with one or more tyrosine kinase inhibitors (such as sorafenib, pazopanib, sunitinib, imatinib, dasatinib, nilotinib, bosutinib, axitinib, and ponatinib).

[0024] In yet another embodiment of any of the methods described herein, the patient has an intra-abdominal tumor.

[0025] In yet another embodiment of any of the methods described herein, the patient is an adult.

[0026] In yet another embodiment of any of the methods described herein, the patient has a family history of familial adenomatous polyposis.

[0027] In yet another embodiment of any of the methods described herein, the patient has a refractory or recurrent disease after previous treatment.

[0028] In yet another embodiment of any of the methods described herein, the patient is treatment-naive.

[0029] In yet another embodiment of any of the methods described herein, the patient is a postmenopausal woman.

[0030] In yet another embodiment of any of the methods described herein, the patient is male (a male patient).

[0031] In yet another embodiment of any of the methods described herein, administration of an acid-reducing agent is avoided or administered 4 hours after administration of nilogacestat or a pharmaceutically acceptable salt thereof.

[0032] Another embodiment is a method for treating desmoid tumors in a patient having a family history of familial adenomatous polyposis, the method comprising orally administering nilogacestat or a pharmaceutically acceptable salt thereof at a dose of 150 mg (free base equivalent dose) twice daily.

[0033] Yet another embodiment is a method for treating desmoid tumors in an untreated patient, the method comprising oral administration of nilogacestat or a pharmaceutically acceptable salt thereof at a dose of 150 mg (free base equivalent dose) twice daily.

[0034] In yet another embodiment of any of the methods described herein, nilogastatin or a pharmaceutically acceptable salt thereof is nilogastatin dihydrobromide.

[0035] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogastatin or a pharmaceutically acceptable salt thereof, the C of nilogastatin max is about 480 to about 950 ng / mL.

[0036] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogastatin or a pharmaceutically acceptable salt thereof, the C of nilogastatin max is about 550 to about 1100 ng / mL.

[0037] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogastatin or a pharmaceutically acceptable salt thereof, the C of nilogastatin max is about 600 to about 800 ng / mL.

[0038] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogastatin or a pharmaceutically acceptable salt thereof, the AUC of nilogastatin last is less than 4000 ng·h / mL. In one embodiment, after the first administration of 150 mg (free base equivalent dose) of nilogastatin or a pharmaceutically acceptable salt thereof, the AUC of nilogastatin last is less than 4000 ng·h / mL and the C of nilogastatin max is about 480 to about 950 ng / mL.

[0039] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogastatin or a pharmaceutically acceptable salt thereof, the AUC of nilogastatin lastis from about 2000 to about 4000 ng·h / mL. In one embodiment, after the first administration of 150 mg (free base equivalent dose) of nilogersat or a pharmaceutically acceptable salt thereof, the AUC of nilogersat last is from about 2000 to about 4000 ng·h / mL, and the C of nilogersat max is from about 480 to about 950 ng / mL.

[0040] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogersat or a pharmaceutically acceptable salt thereof, the AUC of nilogersat inf is less than 4000 ng·h / mL. In one embodiment, after the first administration of 150 mg (free base equivalent dose) of nilogersat or a pharmaceutically acceptable salt thereof, the AUC of nilogersat inf is less than 4000 ng·h / mL, and the C of nilogersat max is from about 480 to about 950 ng / mL.

[0041] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogersat or a pharmaceutically acceptable salt thereof, the AUC of nilogersat inf is from about 2000 to about 4000 ng·h / mL. In one embodiment, after the first administration of 150 mg (free base equivalent dose) of nilogersat or a pharmaceutically acceptable salt thereof, the AUC of nilogersat inf is from about 2000 to about 4000 ng·h / mL, and the C of nilogersat max is from about 480 to about 950 ng / mL.

[0042] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogersat or a pharmaceutically acceptable salt thereof, the AUC of nilogersat inf is from about 2200 to about 4800 ng·h / mL.

[0043] In yet another embodiment of any of the methods described herein, after the first administration of 150 mg (free base equivalent dose) of nilogacestat or a pharmaceutically acceptable salt thereof, the AUC of nilogacestat inf is from about 2200 to about 3300 ng·h / mL.

[0044] In yet another embodiment of any of the methods described herein, in the steady-state exposure where a patient is administered 150 mg (free base equivalent dose) of nilogacestat or a pharmaceutically acceptable salt thereof twice daily, the C max of nilogacestat is from about 1000 to about 1500 ng / mL.

[0045] In yet another embodiment of any of the methods described herein, in the steady-state exposure where a patient is administered 150 mg (free base equivalent dose) of nilogacestat or a pharmaceutically acceptable salt thereof twice daily, the C max of nilogacestat is from about 1100 to about 1400 ng / mL.

[0046] In yet another embodiment of any of the methods described herein, in the steady-state exposure where a patient is administered 150 mg (free base equivalent dose) of nilogacestat or a pharmaceutically acceptable salt thereof twice daily, the AUC of nilogacestat tau is from about 5000 to about 8000 ng·h / mL.

[0047] In yet another embodiment of any of the methods described herein, in the steady-state exposure where a patient is administered 150 mg (free base equivalent dose) of nilogacestat or a pharmaceutically acceptable salt thereof twice daily, the AUC of nilogacestat tau is from about 6000 to about 7000 ng·h / mL.

[0048] In one embodiment of the aforementioned method, in the treatment of a patient, nilogicitat or a pharmaceutically acceptable salt thereof is administered at a dose of 100 mg (free base equivalent dose) twice a day. However, in the case of certain adverse reactions, the administration of nilogicitat or a pharmaceutically acceptable salt thereof is reduced to 50 mg (free base equivalent dose) twice a day.

[0049] The compound of formula (I) [Chemical formula] Or a composition comprising a pharmaceutically acceptable salt thereof, wherein the composition provides an average maximum drug plasma concentration (C rax ) exceeding 100 ng / ml is described herein.

[0050] Furthermore, disclosed herein is a method for treating desmoid tumors, the method comprising administering to a patient in need thereof an oral dosage form comprising 50 mg of nilogicitat or a pharmaceutically acceptable salt thereof.

[0051] Also disclosed herein is a method for treating desmoid tumors in a patient in need thereof, the method comprising administering to the patient a 50 mg oral dosage of nilogicitat or a pharmaceutically acceptable salt thereof, wherein the oral dosage form provides an average maximum drug plasma concentration (C max ) exceeding 100 ng / ml.

[0052] Furthermore, in a patient in need of treatment for desmoid tumors, a method for treating desmoid tumors, the method comprising administering to the patient a 50 mg oral dosage of nilogicitat or a pharmaceutically acceptable salt thereof, wherein the oral dosage form provides a plasma area under the curve (AUC inf ) less than 700 ng·h / ml.

[0053] A method for treating desmoid tumors, which comprises administering to a patient in need thereof nilotinib or a pharmaceutically acceptable salt thereof at a dose of 300 mg per day, is also disclosed herein.

[0054] Furthermore, disclosed herein is a method for treating desmoid tumors in a patient in need thereof, the method comprising administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation provides an average maximum drug plasma concentration (C max ) exceeding 100 ng / ml.

[0055] Also disclosed herein is a method for treating desmoid tumors in a patient in need thereof, the method comprising administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation provides an area under the plasma curve (AUC inf ) of less than 700 ng·h / ml.

[0056] In addition, a method for treating multiple myeloma, which comprises administering to a patient in need thereof nilotinib or a pharmaceutically acceptable salt thereof at a dose of 200 mg per day, is disclosed herein.

[0057] Also, a method for treating multiple myeloma, which comprises administering to a patient in need thereof nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg per day, is disclosed herein.

[0058] Disclosed herein is also a method for treating multiple myeloma, which comprises administering to a patient in need thereof 200 mg of nilotinib or a pharmaceutically acceptable salt thereof once a day.

[0059] Furthermore, a method for treating multiple myeloma, the method comprising administering to a patient in need thereof 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof once daily.

[0060] Also disclosed herein is a method for treating multiple myeloma, the method comprising administering to a patient in need thereof 100 mg of nilotinib or a pharmaceutically acceptable salt thereof once daily.

[0061] Furthermore, disclosed herein is a method for treating multiple myeloma, the method comprising administering to a patient in need thereof 50 mg of nilotinib or a pharmaceutically acceptable salt thereof once daily.

[0062] Also, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma, the method comprising administering to the patient an oral formulation of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation results in an average maximum drug plasma concentration (C max ) exceeding 100 ng / ml.

[0063] Furthermore, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma, the method comprising administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation results in an average maximum drug plasma concentration (C max ) exceeding 225 ng / ml.

[0064] Also disclosed herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient an oral formulation of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation results in an area under the plasma curve (AUC inf ) of less than 700 ng·h / ml.

[0065] Furthermore, provided herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation provides a plasma area under the curve (AUC inf ) of less than 3000 ng·h / ml.

[0066] Also provided herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation provides an average maximum drug plasma concentration (C max ) of greater than 100 ng / ml.

[0067] Further provided herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation provides an average maximum drug plasma concentration (C max ) of greater than 225 ng / ml.

[0068] Furthermore, provided herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation provides a plasma area under the curve (AUC inf ) of less than 700 ng·h / ml.

[0069] Also provided herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof, wherein the oral formulation provides a plasma area under the curve (AUC inf ) of less than 3000 ng·h / ml.

[0070] Also disclosed herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient a single oral dose of niraparstat or a pharmaceutically acceptable salt thereof for co-treatment of multiple myeloma.

[0071] Also disclosed herein is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient an oral dose of niraparstat or a pharmaceutically acceptable salt thereof in combination with belantamab mafodotin.

[0072] Yet another embodiment is a method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient (i) niraparstat or a pharmaceutically acceptable salt thereof and (ii) one or more additional active ingredients for treating multiple myeloma (e.g., BCMA therapy (e.g., intravenous administration)) in combination, wherein the method comprises (A) orally administering to the patient 150 mg (free base equivalent dose) of niraparstat or a pharmaceutically acceptable salt thereof twice daily and (B) comprising one or more of the following: (a) For patients in whom grade 3 diarrhea persists for at least 3 days despite maximal medical treatment, withholding niraparstat or a pharmaceutically acceptable salt thereof until the diarrhea is grade 1 or less or has recovered to baseline, and then restarting oral administration of niraparstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (b) For patients with grade 3 folliculitis, withholding niraparstat or a pharmaceutically acceptable salt thereof until the folliculitis is grade 1 or less or has recovered to baseline, and then restarting oral administration of niraparstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (c) For patients with grade 3 maculopapular rash, withhold nilotinib or a pharmaceutically acceptable salt thereof until the maculopapular rash has recovered to grade 1 or lower maculopapular rash or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent amount) twice daily. (d) For patients with grade 3 hidradenitis, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hidradenitis has recovered to grade 1 or lower hidradenitis or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (e) For patients in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hypophosphatemia has recovered to grade 1 or lower hypophosphatemia or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent amount) twice daily. (f) For patients with grade 3 hypokalemia despite maximum replacement therapy, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hypokalemia has recovered to grade 1 or lower hypokalemia or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (g) For patients in whom alanine transaminase (ALT) or aspartate aminotransferase (AST) is 3 to 5 times the upper limit of the reference range (ULN), discontinue nilotuzumab or a pharmaceutically acceptable salt thereof until ALT, AST, or both are less than or equal to 3 times the ULN or have recovered to baseline, and then resume oral administration of nilotuzumab or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. In one preferred embodiment, the patient is administered in combination with BCMA therapy. In another embodiment, the method further comprises one or more of the following: (h) permanently discontinuing treatment with nilotuzumab or a pharmaceutically acceptable salt thereof for patients having ALT or AST greater than 5 times the ULN; (i) permanently discontinuing treatment with nilotuzumab or a pharmaceutically acceptable salt thereof for patients having anaphylaxis or other severe allergic reactions; and (j) in the case of another severe adverse reaction or a life-threatening adverse reaction, discontinuing nilotuzumab or a pharmaceutically acceptable salt thereof until the adverse reaction is a grade 1 or less adverse reaction or has recovered to baseline, and then, after careful consideration of the potential benefits and the likelihood of recurrence of the adverse reaction, (A) resume oral administration of nilotuzumab or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (B) if a severe or life-threatening adverse reaction recurs at a dose of 100 mg (free base equivalent dose) twice daily, permanently discontinue treatment with nilotuzumab or a pharmaceutically acceptable salt thereof.

[0073] Yet another embodiment is a method for treating multiple myeloma in a patient in need thereof, the treatment comprising co-administering to the patient (i) nilotuzumab or a pharmaceutically acceptable salt thereof, and (ii) one or more active ingredients for the treatment of multiple myeloma (e.g., BCMA therapy), the method comprising (A) orally administering to the patient nilotuzumab or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (B) one or more of the following: (a) For patients with grade 3 diarrhea that persists for at least 3 days despite maximum medical treatment, withhold nilotinib or a pharmaceutically acceptable salt thereof until the diarrhea resolves to grade 1 or less diarrhea or returns to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily. (b) For patients with grade 3 folliculitis, withhold nilotinib or a pharmaceutically acceptable salt thereof until the folliculitis resolves to grade 1 or less folliculitis or returns to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily. (c) For patients with grade 3 maculopapular rash, withhold nilotinib or a pharmaceutically acceptable salt thereof until the maculopapular rash resolves to grade 1 or less maculopapular rash or returns to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily. (d) For patients with grade 3 hidradenitis, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hidradenitis resolves to grade 1 or less hidradenitis or returns to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily. (e) For patients with grade 3 hypophosphatemia that persists for at least 7 days despite maximum replacement therapy, withhold nilotinib or a pharmaceutically acceptable salt thereof until the hypophosphatemia resolves to grade 1 or less or returns to baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily. (f) In patients with grade 3 hypokalemia, despite maximum replacement therapy, withhold nilotolisib or a pharmaceutically acceptable salt thereof until the hypokalemia is grade 1 or lower hypokalemia or has recovered to baseline, and then resume oral administration of nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily, and (g) If a patient's alanine transaminase (ALT) or aspartate aminotransferase (AST) is 3 to 5 times the upper limit of the reference range (ULN), withhold nilotolisib or a pharmaceutically acceptable salt thereof until ALT, AST, or both are 3 times or less the ULN or have recovered to baseline, and then resume oral administration of nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily. A method comprising: In one preferred embodiment, the patient is administered in combination with BCMA therapy. In another embodiment, the method further comprises one or more of the following: (h) Permanently discontinue treatment with nilotolisib or a pharmaceutically acceptable salt thereof in patients with ALT or AST greater than 5 times the ULN, and (i) Permanently discontinue treatment with nilotolisib or a pharmaceutically acceptable salt thereof in patients with anaphylaxis or other severe allergic reactions, and (j) In the case of another severe adverse reaction or a life-threatening adverse reaction, withhold nilotolisib or a pharmaceutically acceptable salt thereof until the adverse reaction is grade 1 or lower or has recovered to baseline, and then, after carefully considering the potential benefits and the likelihood of recurrence of the adverse reaction, (A) Resume oral administration of nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (B) If a severe or life-threatening adverse reaction recurs at a dose of 50 mg (free base equivalent dose) twice daily, permanently discontinue treatment with nilotolisib or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the pharmaceutically acceptable salt form of nilogacestat in the compositions, dosage forms, or methods of treatment described herein is the hydrobromide salt form. In some embodiments, the hydrobromide salt form is the dihydrobromide salt form.

[0075] In some embodiments, the composition or dosage form is administered orally to a human. In some embodiments, the composition or dosage form is in solid form. In some embodiments, the composition or dosage form is in the form of a tablet or a capsule.

[0076] In yet another embodiment of any of the methods described herein, one or more antiemetics and / or one or more antidiarrheals can be administered to a patient during treatment with nilogacestat. BRIEF DESCRIPTION OF THE DRAWINGS

[0077]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Mode for Carrying Out the Invention

[0078] I. Definitions To facilitate the understanding of the disclosure described herein, several terms are defined below.

[0079] Generally, the nomenclature used herein, as well as the experimental procedures of organic chemistry, medicinal chemistry, and pharmacology described herein, are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0080] In this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more" and "at least one", may be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single". In other embodiments, the term "a" or "an" includes "two or more" or "plural".

[0081] Furthermore, the "and / or" used herein should be construed as specific disclosure of each of the two specified features or components, whether or not there are others. Thus, the term "and / or" used in phrases such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0082] The term "nilogastat" refers to the single enantiomer (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentaamide. A preferred pharmaceutically acceptable salt of nilogastat is nilogastat dihydrobromide (also referred to as nilogastat hydrobromide). The dosage of nilogastat or its salt is all in terms of the free base amount. For example, 150 mg of nilogastat dihydrobromide refers to nilogastat dihydrobromide corresponding to 150 mg of the free base amount of nilogastat (i.e., approximately 199.6 mg of nilogastat dihydrobromide).

[0083] The term "subject" refers to animals including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein with reference to mammalian subjects such as, for example, human subjects.

[0084] As used herein, the terms "treat," "treated," and "treating" mean both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow down (mitigate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Thus, those in need of treatment include those already diagnosed with a disorder or those suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, symptom relief, whether detectable or undetectable; a decrease in the extent of a condition, disorder, or disease; a stabilization (i.e., not worsening) of a condition, disorder, or disease; a delay or slowing in the onset of progression of a condition, disorder, or disease; an improvement or remission (partial or complete) of a condition, disorder, or disease state; an improvement in at least one measurable physical parameter not necessarily distinguishable by the patient; or an enhancement or improvement of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without undue levels of side effects. Treatment also includes prolonging survival as compared to a predicted survival time in the absence of treatment. The term "therapeutically effective amount" means an amount of a compound that, when administered, is sufficient to prevent or alleviate the onset of one or more of the symptoms of the disorder, disease, or condition being treated. The term "treatment effective amount" also refers to an amount of a compound that is sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human being sought by a researcher, veterinarian, physician, or clinician.

[0085] In certain embodiments, a subject is considered to have “responded” to treatment of cancer, such as multiple myeloma, if, according to the methods of the invention, the patient shows a decrease or complete disappearance in the number of cancer cells, a reduction in one or more symptoms associated with a particular cancer, a decrease in morbidity and mortality, an improvement in quality of life, a progression-free survival period (“PFS”), a disease-free survival period (“DFS”), an overall survival period (“OS”), a metastasis-free survival period (“MFS”), a complete response (“CR”), minimal residual disease (“MRD”), a partial response (“PR”), stable disease (“SD”), a decrease in progressive disease (“PD”), an increase in time to progression (“TTP”), or any combination thereof. In some embodiments, the standard of care results approved domestically or internationally for a given cancer are used to determine whether a therapeutically effective amount of nilotinib or a pharmaceutically acceptable salt thereof meets any of these particular endpoints (e.g., CR, PFS, PR).

[0086] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier", or "physiologically acceptable excipient" refer to pharmaceutically acceptable materials, compositions, or vehicles such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other components of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs in a state where it has a reasonable benefit / risk ratio without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0087] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of Compound A or Compound B. These salts can be prepared in the manufacturing process of the dosage vehicle or dosage form, in situ, or by reacting the purified compound of the present invention in its free base form separately with a suitable organic or inorganic acid, and then isolating the salts formed during subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate, etc. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0088] Pharmaceutically acceptable salts of the subject compounds include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionic acid, etc.

[0089] In certain embodiments, because the compounds of the invention may contain one or more acidic functional groups, they can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to relatively non-toxic inorganic and organic base addition salts of the compounds of the invention. These salts can likewise be prepared in situ in the manufacturing process of a dosage vehicle or form, or by separately reacting the purified compound in its free acid form with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, among others. Representative organic amines useful in the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, e.g., Berge et al., supra).

[0090] The term "intraperitoneal tumor" includes not only patients having intraperitoneal tumors (including, for example, those in the mesentery or pelvis), but also patients having multiple target tumors both intraperitoneally and extraperitoneally.

[0091] The term "baseline" refers to an initial measurement of a condition that is obtained at an early time point and used for comparison to examine changes over time. A baseline can be a measurement taken immediately prior to treatment and can then serve as a measurement to confirm whether a treatment effect has occurred. For example, the size of a tumor can be measured before treatment (baseline) and after treatment, and then subsequently measured to confirm whether there has been a treatment effect.

[0092] The terms "about" or "approximately" mean an acceptable error for a particular value as determined by one of ordinary skill in the art, which error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0093] The term "untreated patient" refers to a patient who has a particular disease or disorder (such as desmoid tumor or multiple myeloma) and has not received treatment for that disease or disorder. In one embodiment, the untreated patient has not had surgery. In another embodiment, the untreated patient has not received treatment with a pharmaceutical. In an exemplary embodiment, the untreated patient has no history of treatment with a tyrosine kinase inhibitor such as sorafenib.

[0094] Unless the context dictates otherwise, the terms "comprise", "comprises", and "comprising" should be construed inclusively rather than exclusively, and the applicant uses each of these terms based on the clear understanding that they are intended to be construed in that manner when interpreting this patent, including the following claims.

[0095] II. Compositions The present disclosure relates to a composition comprising a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof, which composition provides an average maximum drug plasma concentration (C max ) exceeding 100 ng / ml. In some aspects, the composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof has an average maximum drug plasma concentration (C max) results in. In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof has an average maximum drug plasma concentration (C max ) results in. In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof has an average maximum drug plasma concentration (C max ) results in. In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof has an average maximum drug plasma concentration (C max ) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml.

[0096] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrobromide salt. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a dihydrobromide salt.

[0097] In some embodiments, the composition comprises the compound of formula (I) in dihydrobromide form and results in an average maximum drug plasma concentration (C max ) exceeding 100 ng / ml. In some embodiments, the composition comprises the compound of formula (I) in dihydrobromide form and results in an average maximum drug plasma concentration (C max ) of about 150 ng / ml to about 500 ng / ml. In some embodiments, the composition comprises the compound of formula (I) in dihydrobromide form and results in an average maximum drug plasma concentration (C max ) of about 200 ng / ml to about 450 ng / ml. In some embodiments, the composition comprises the compound of formula (I) in dihydrobromide form and results in an average maximum drug plasma concentration (C max) results in. In some embodiments, the composition comprises the compound of formula (I) in hydrobromide form and has an average maximum drug plasma concentration (C max ) that results in.

[0098] A composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) can be administered to a subject via oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intracardiac, and infusion techniques), rectal, intranasal, topical, or transdermal (e.g., by use of a patch) routes. In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) can be administered orally to a subject.

[0099] In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) is in solid form. In one embodiment, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) is a tablet or a capsule.

[0100] In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form) can further comprise one or more pharmaceutically acceptable excipients. For example, for oral administration, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate, and glycine can be used with various disintegrants such as starch (preferably corn, potato or tapioca starch), methylcellulose, alginic acid, and certain complex silicates, and can be included within tablets together with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting. Similar types of solid compositions can also be used as fillers for gelatin capsules. In this regard, preferred materials include high molecular weight polyethylene glycol in addition to lactose or milk sugar. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be mixed with various sweetening, flavoring, coloring or dyeing agents, and, optionally, similarly emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof.

[0101] In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) can be administered to a patient in need thereof for the treatment of desmoid tumors or multiple myeloma. The composition can comprise the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) in an amount in the range of, for example, about 25 mg to 350 mg, 50 mg to 325 mg, 75 mg to 300 mg, 100 mg to 275 mg, 125 mg to 250 mg, 150 mg to 225 mg, 175 mg to 200 mg. In some embodiments, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) can be administered in the range of, for example, about 50 mg to 300 mg, 100 mg to 250 mg, and 150 mg to 200 mg. The composition can comprise the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) in amounts of, for example, about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, and 350 mg. In some embodiments, the composition can comprise the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form) in amounts of, for example, about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 350 mg. In some embodiments, the composition can be administered once daily. In other embodiments, the composition can be administered twice daily. For example, the composition can comprise 50 mg of nilotinib or a pharmaceutically acceptable salt thereof and can be administered once daily. In other examples, the composition can comprise 50 mg of nilotinib or a pharmaceutically acceptable salt thereof and can be administered twice daily. The composition can comprise 100 mg of nilotinib or a pharmaceutically acceptable salt thereof and can be administered once daily. In other examples, the composition can comprise 100 mg of nilotinib or a pharmaceutically acceptable salt thereof and can be administered twice daily. In other examples, the composition can comprise 150 mg of nilotinib or a pharmaceutically acceptable salt thereof and can be administered once daily. In other examples, the composition can comprise 150 mg of nilotinib or a pharmaceutically acceptable salt thereof and can be administered twice daily.

[0102] In one embodiment, it is a solid oral pharmaceutical composition (such as a tablet or capsule) containing 50 mg (free base equivalent dose) of nilogersstat or a pharmaceutically acceptable salt thereof (such as nilogersstat dihydrobromide), which, upon first oral administration to a human subject, results in a C max of less than 200 ng / mL (for example, less than 190 ng / mL). In one embodiment, the solid pharmaceutical composition results in a C max of about 100 to about 200 ng / mL upon first oral administration to a human subject.

[0103] In another embodiment, it is a solid oral pharmaceutical composition (such as a tablet or capsule) containing 50 mg (free base equivalent dose) of nilogersstat or a pharmaceutically acceptable salt thereof (such as nilogersstat dihydrobromide), which, upon first oral administration to a human subject, results in an AUC last of less than 725 ng·h / mL. In one embodiment, the solid oral pharmaceutical composition shows a C max of less than 200 ng / mL (for example, less than 190 ng / mL, or about 100 to about 200 ng / mL) upon first oral administration to a human subject.

[0104] In yet another embodiment, it is a solid oral pharmaceutical composition (such as a tablet or capsule) containing 50 mg (free base equivalent dose) of nilogersstat or a pharmaceutically acceptable salt thereof (such as nilogersstat dihydrobromide), which, upon first oral administration to a human subject, results in an AUC last of about 375 to about 725 ng·h / mL. In one embodiment, the solid oral pharmaceutical composition shows a C max of less than 200 ng / mL (for example, less than 190 ng / mL, or about 100 to about 200 ng / mL) upon first oral administration to a human subject.

[0105] Yet another embodiment is an AUC upon first oral administration to a human subject infA solid oral pharmaceutical composition (such as a tablet or capsule) containing 50 mg (equivalent dose of free base) of nilogacestat or a pharmaceutically acceptable salt thereof (such as nilogacestat dihydrobromide) and having a C of less than 725 ng·h / mL. In one embodiment, the solid oral pharmaceutical composition has a C of less than 200 ng / mL (e.g., less than 190 ng / mL, or about 100 to about 200 ng / mL) at the first oral administration to a human subject. max is shown.

[0106] Yet another embodiment is a solid oral pharmaceutical composition (such as a tablet or capsule) containing 50 mg (equivalent dose of free base) of nilogacestat or a pharmaceutically acceptable salt thereof (such as nilogacestat dihydrobromide) and having an AUC of about 375 to 725 ng·h / mL at the first oral administration to a human subject. In one embodiment, the solid oral pharmaceutical composition has a C of less than 200 ng / mL (e.g., less than 190 ng / mL, or about 100 to about 200 ng / mL) at the first oral administration to a human subject. inf is shown. max is shown.

[0107] One embodiment is a solid oral pharmaceutical composition (such as a tablet or capsule) containing 100 mg (equivalent dose of free base) of nilogacestat or a pharmaceutically acceptable salt thereof (such as nilogacestat dihydrobromide) and having a C of less than 600 ng·h / mL (less than 570 ng / mL, or about 300 to about 570 ng / mL, etc.) at the first oral administration to a human subject. max is shown.

[0108] Another embodiment is a solid oral pharmaceutical composition (such as a tablet or capsule) containing 100 mg (equivalent dose of free base) of nilogacestat or a pharmaceutically acceptable salt thereof (such as nilogacestat dihydrobromide) and having an AUC of less than 2300 ng·h / mL at the first oral administration to a human subject. In one embodiment, the solid oral pharmaceutical composition has a C of less than 600 ng / mL (e.g., less than 570 ng / mL, or about 300 to about 570 ng / mL) at the first oral administration to a human subject. last is shown. max is shown.

[0109] Yet another embodiment is a solid oral pharmaceutical composition (such as a tablet or capsule) comprising 100 mg (free base equivalent dose) of nilogicstat or a pharmaceutically acceptable salt thereof (such as nilogicstat dihydrobromide) which results in an AUC of about 1200 to 2300 ng·h / mL upon first oral administration to a human subject. In one embodiment, the solid oral pharmaceutical composition exhibits a C last of less than 600 ng / mL (for example, less than 570 ng / mL, or about 300 to about 570 ng / mL) upon first oral administration to a human subject. max

[0110] Another embodiment is a solid oral pharmaceutical composition (such as a tablet or capsule) comprising 100 mg (free base equivalent dose) of nilogicstat or a pharmaceutically acceptable salt thereof (such as nilogicstat dihydrobromide) which results in an AUC of less than 2300 ng·h / mL upon first oral administration to a human subject. In one embodiment, the solid oral pharmaceutical composition exhibits a C inf of less than 600 ng / mL (for example, less than 570 ng / mL, or about 300 to about 570 ng / mL) upon first oral administration to a human subject. max

[0111] Yet another embodiment is a solid oral pharmaceutical composition (such as a tablet or capsule) comprising 100 mg (free base equivalent dose) of nilogicstat or a pharmaceutically acceptable salt thereof (such as nilogicstat dihydrobromide) which results in an AUC of about 1200 to 2300 ng·h / mL upon first oral administration to a human subject. In one embodiment, the solid oral pharmaceutical composition exhibits a C inf of less than 600 ng / mL (for example, less than 570 ng / mL, or about 300 to about 570 ng / mL) upon first oral administration to a human subject. max

[0112] One embodiment is a C max ​​​A solid oral pharmaceutical composition (such as a tablet or capsule) containing 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof (such as nilotinib dihydrobromide) with an AUC of less than 1000 ng·h / mL (less than 950 ng / mL, or about 480 to about 950 ng / mL, etc.).

[0113] Another embodiment is an AUC upon first oral administration to a human subject last A solid oral pharmaceutical composition (such as a tablet or capsule) containing 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof (such as nilotinib dihydrobromide) with an AUC of less than 4000 ng·h / mL. In one embodiment, the solid oral pharmaceutical composition has a C of less than 1000 ng / mL (e.g., less than 950 ng / mL, or about 480 to about 950 ng / mL) upon first oral administration to a human subject max as shown.

[0114] Yet another embodiment is an AUC upon first oral administration to a human subject last A solid oral pharmaceutical composition (such as a tablet or capsule) containing 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof (such as nilotinib dihydrobromide) with an AUC of about 2000 to 4000 ng·h / mL. In one embodiment, the solid oral pharmaceutical composition has a C of less than 1000 ng / mL (e.g., less than 950 ng / mL, or about 480 to about 950 ng / mL) upon first oral administration to a human subject max as shown.

[0115] Another embodiment is an AUC upon first oral administration to a human subject inf A solid oral pharmaceutical composition (such as a tablet or capsule) containing 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof (such as nilotinib dihydrobromide) with an AUC of less than 4000 ng·h / mL. In one embodiment, the solid oral pharmaceutical composition has a C of less than 1000 ng / mL (e.g., less than 950 ng / mL, or about 480 to about 950 ng / mL) upon first oral administration to a human subject max as shown.

[0116] Yet another embodiment is a solid oral pharmaceutical composition (such as a tablet or capsule) containing 150 mg (free base equivalent dose) of nilogacestat or a pharmaceutically acceptable salt thereof (such as nilogacestat dihydrobromide) that results in an AUC of about 2000 - 4000 ng·h / mL upon first oral administration to a human subject. In one embodiment, the solid oral pharmaceutical composition exhibits a C inf of less than 1000 ng / mL (e.g., less than 950 ng / mL, or about 480 - about 950 ng / mL) upon first oral administration to a human subject. max is shown.

[0117] III. Methods of Treatment A. Desmoid Tumors Nilogacestat can be administered to a patient to treat desmoid tumors. In some embodiments, in a patient in need of treatment for desmoid tumors, a method for treating desmoid tumors includes administering to the patient an oral dosage form of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dosage form results in an average maximum drug plasma concentration (C max ) that exceeds 100 ng / ml. In some embodiments, in a patient in need of treatment for desmoid tumors, a method for treating desmoid tumors includes administering to the patient an oral dosage form of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dosage form results in an average maximum drug plasma concentration (C max ) of about 150 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treatment for desmoid tumors, a method for treating desmoid tumors includes administering to the patient an oral dosage form of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dosage form results in an average maximum drug plasma concentration (C max) results. In some embodiments, in a patient in need of treatment for a desmoid tumor, a method for treating the desmoid tumor comprises administering to the patient an oral formulation of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) results. In some embodiments, in a patient in need of treatment for a desmoid tumor, a method for treating the desmoid tumor comprises administering to the patient an oral formulation of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral formulation results in an average maximum drug plasma concentration (C of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml max ) results.

[0118] In some embodiments, in a patient in need of treatment for a desmoid tumor, a method for treating the desmoid tumor comprises administering to the patient an oral formulation of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral formulation results in an area under the plasma curve (AUC inf ) of less than 700 ng·h / ml. In some embodiments, in a patient in need of treatment for a desmoid tumor, a method for treating the desmoid tumor comprises administering to the patient an oral formulation of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral formulation results in an area under the plasma curve (AUC inf) results in. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) results in. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) results in. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC of about 200 ng·h / ml, about 225 ng·h / ml, about 250 ng·h / ml, about 275 ng·h / ml, about 300 ng·h / ml, about 325 ng·h / ml, about 350 ng·h / ml, about 375 ng·h / ml, about 400 ng·h / ml, about 425 ng·h / ml, about 450 ng·h / ml, about 475 ng·h / ml, about 500 ng·h / ml, about 525 ng·h / ml, about 550 ng·h / ml, about 575 ng·h / ml, about 600 ng·h / ml, about 625 ng·h / ml, or about 675 ng·h / ml inf ) results in.

[0119] In some embodiments, a method for treating a desmoid tumor comprises administering to a patient in need thereof an oral dosage form comprising 50 mg of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form).

[0120] In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of 50 mg of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) that exceeds 100 ng / ml. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of 50 mg of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 150 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of 50 mg of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 200 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of 50 mg of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 250 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating a desmoid tumor comprises administering to the patient an oral formulation of 50 mg of nilogacestat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml.

[0121] In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating the desmoid tumor includes administering to the patient an oral dosage form of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral dosage form results in a plasma area under the curve (AUC inf ) of less than 700 ng·h / ml. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating the desmoid tumor includes administering to the patient an oral dosage form of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral dosage form results in a plasma area under the curve (AUC inf ) of from about 200 ng·h / ml to about 650 ng·h / ml. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating the desmoid tumor includes administering to the patient an oral dosage form of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral dosage form results in a plasma area under the curve (AUC inf ) of from about 250 ng·h / ml to about 650 ng·h / ml. In some embodiments, in a patient in need of treatment of a desmoid tumor, a method for treating the desmoid tumor includes administering to the patient an oral dosage form of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral dosage form results in a plasma area under the curve (AUC inf) results in. In some embodiments, in a patient in need of treatment for a desmoid tumor, a method for treating the desmoid tumor comprises administering to the patient an oral dose of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral dose results in a plasma area under the curve (AUC inf ) of about 200 ng·h / ml, about 225 ng·h / ml, about 250 ng·h / ml, about 275 ng·h / ml, about 300 ng·h / ml, about 325 ng·h / ml, about 350 ng·h / ml, about 375 ng·h / ml, about 400 ng·h / ml, about 425 ng·h / ml, about 450 ng·h / ml, about 475 ng·h / ml, about 500 ng·h / ml, about 525 ng·h / ml, about 550 ng·h / ml, about 575 ng·h / ml, about 600 ng·h / ml, about 625 ng·h / ml, or about 675 ng·h / ml.

[0122] In some embodiments, in a patient in need of treatment for a desmoid tumor, a method for treating the desmoid tumor comprises administering to the patient 300 mg / day of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt).

[0123] In some embodiments, a method for treating a desmoid tumor comprises orally administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt). In some embodiments, a method for treating a desmoid tumor comprises orally administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) as a solid dosage form. In some embodiments, the solid dosage form is a tablet or a capsule.

[0124] In some embodiments, a method for treating a desmoid tumor comprises administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) once daily. In some embodiments, a method for treating a desmoid tumor comprises administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) two, three, or four times daily. When nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) is administered multiple times daily, the total daily dose administered each time may be the same or different. For example, when 300 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) is administered twice daily, the patient may be administered a dose of 150 mg twice (e.g., once at 8:00 a.m. and once at 8:00 p.m.), or may be administered a dose of 100 mg in the morning and a dose of 200 mg in the evening. Each administration may be composed of multiple solid dosage forms. For example, an individual dose of 150 mg (i.e., the morning dose of the total daily dose of 300 mg administered in two divided doses) can be administered as three 50 mg tablets.

[0125] In one embodiment, a patient having a desmoid tumor is administered 150 mg of nilotinib twice daily (total dose of 300 mg of nilotinib). In a preferred embodiment, nilotinib is administered in the form of its dihydrobromide salt. In a preferred embodiment, the dose is changed as follows in response to adverse reactions:

[0126] In one embodiment, as described in Table 1 below, the dose is changed for the selected severe adverse reactions. All adverse reactions or events are graded according to the "Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE v5.0)" of the National Cancer Institute of the United States, which is incorporated herein by reference. For adverse events (or adverse reactions) not described in CTCAE or severe adverse events, the following evaluation system was used: Grade 1 refers to mild, i.e., asymptomatic or mild symptoms, with only clinical or diagnostic observation and no treatment indicated. Grade 3 refers to severe or medically significant but not immediately life-threatening, requiring hospitalization or an extended hospital stay, and restriction of activities of daily living around the body. Activities of daily living around the body refer to a state where bathing, dressing and undressing, food intake, toilet use, and taking medicine orally are possible and not bedridden.

Table 1

[0127] ALT refers to alanine transaminase, AST refers to aspartate aminotransferase, and ULN refers to the upper limit of the reference range.

[0128] In a further embodiment, in the case of severe adverse reactions other than those in Table 1, or in the case of life-threatening adverse reactions, nilogasostat is discontinued until the reaction resolves to Grade 1 or below or baseline. Treatment with nilogasostat can be restarted at a dose of 100 mg twice a day, taking into account the potential benefits and the possibility of recurrence of adverse reactions. Nilogasostat is permanently discontinued if severe or life-threatening adverse reactions recur when re-induced at a reduced dose (i.e., 100 mg twice a day).

[0129] B. Multiple Myeloma Nilogasostat can be administered to patients for the treatment of multiple myeloma.

[0130] In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the hydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) that exceeds 100 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the hydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 150 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the hydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 200 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the hydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 250 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the hydrobromide salt), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml.

[0131] In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation provides an average maximum drug plasma concentration (C max ) that exceeds 225 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation provides an average maximum drug plasma concentration (C max ) of from about 250 ng / ml to about 750 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation provides an average maximum drug plasma concentration (C max ) of from about 300 ng / ml to about 750 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), wherein the oral formulation provides an average maximum drug plasma concentration (C max ) of from about 350 ng / ml to about 750 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt), the oral formulation having an average maximum drug plasma concentration (C max) results in.

[0132] In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) less than 700 ng·h / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) of about 200 ng·h / ml to about 650 ng·h / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) of about 250 ng·h / ml to about 650 ng·h / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf)resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage form results in an area under the plasma curve (AUC inf )resulting.

[0133] In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf )less than 3000 ng·h / ml. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf )in the range of about 200 ng·h / ml to about 2950 ng·h / ml. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) of from about 300 ng·h / ml to about 2950 ng·h / ml inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) of from about 350 ng·h / ml to about 2950 ng·h / ml inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) of from about 400 ng·h / ml to about 2950 ng·h / ml inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) of from about 450 ng·h / ml to about 2950 ng·h / ml inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) of from about 500 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form provides a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form provides a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form provides a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form provides a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form provides a plasma area under the curve (AUC inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in the body of from about 800 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in the body of from about 850 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in the body of from about 900 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in the body of from about 950 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in the body of from about 1000 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1050 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1100 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1150 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1200 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1250 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) in vivo of from about 1350 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) in vivo of from about 1400 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) in vivo of from about 1450 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) in vivo of from about 1500 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) in vivo of from about 1550 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC inf)resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1850 ng·h / ml to about 2950 ng·h / ml inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1900 ng·h / ml to about 2950 ng·h / ml inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 1950 ng·h / ml to about 2950 ng·h / ml inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 2000 ng·h / ml to about 2950 ng·h / ml inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation provides a plasma area under the curve (AUC) of from about 2050 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in vivo of from about 2100 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in vivo of from about 2150 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in vivo of from about 2200 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in vivo of from about 2250 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form), wherein the oral dosage form results in a plasma area under the curve (AUC) in vivo of from about 2300 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in an area under the in vivo plasma curve (AUC) of from about 2350 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in an area under the in vivo plasma curve (AUC) of from about 2400 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in an area under the in vivo plasma curve (AUC) of from about 2450 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in an area under the in vivo plasma curve (AUC) of from about 2500 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in an area under the in vivo plasma curve (AUC) of from about 2550 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) of about 2600 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) of about 2650 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) of about 2700 ng·h / ml to about 2950 ng·h / ml inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma includes administering to the patient an oral formulation of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC) of about 2750 ng·h / ml to about 2950 ng·h / ml inf) results. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of niraparstat or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide dihydrate form), the oral dosage form having about 200 ng·h / ml, about 225 ng·h / ml, about 250 ng·h / ml, about 275 ng·h / ml, about 300 ng·h / ml, about 325 ng·h / ml, about 350 ng·h / ml, about 375 ng·h / ml, about 400 ng·h / ml, about 425 ng·h / ml, about 450 ng·h / ml, about 475 ng·h / ml, about 500 ng·h / ml, about 525 ng·h / ml, about 550 ng·h / ml, about 575 ng·h / ml, about 600 ng·h / ml, about 625 ng·h / ml, about 675 ng·h / ml, about 700 ng·h / ml, about 725 ng·h / ml, about 750 ng·h / ml, about 775 ng·h / ml, about 800 ng·h / ml, about 825 ng·h / ml, about 850 ng·h / ml, about 875 ng·h / ml, about 900 ng·h / ml, about 925 ng·h / ml, about 950 ng·h / ml, about 975 ng·h / ml, about 1000 ng·h / ml, about 1025 ng·h / ml, about 1050 ng·h / ml, about 1075 ng·h / ml, about 1100 ng·h / ml, about 1125 ng·h / ml, about 1150 ng·h / ml, about 1175 ng·h / ml, about 1200 ng·h / ml, about 1225 ng·h / ml, about 1250 ng·h / ml, about 1275 ng·h / ml, about 1300 ng·h / ml, about 1325 ng·h / ml, about 1350 ng·h / ml, about 1375 ng·h / ml, about 1400 ng·h / ml, about 1425 ng·h / ml, about 1450 ng·h / ml, about 1475 ng·h / ml, about 1500 ng·h / ml, about 1525 ng·h / ml, about 1550 ng·h / ml, about 1575 ng·h / ml, about 1600 ng·h / ml, about 1625 ng·h / ml, about 1650 ng·h / ml, about 1675 ng·h / ml, about 1700 ng·h / ml, about 1725 ng·h / ml, about 1750 ng·h / ml, about 1775 ng·h / ml, about 1800 ng·h / ml, about 1825 ng·h / ml, about 1850 ng·h / ml, about 1875 ng·h / ml, about 1900 ng·h / ml, about 1925 ng·h / ml, about 1950 ng·h / ml,resulting in a plasma area under the curve (AUC, inf ) of about 2000 ng·h / ml, about 2025 ng·h / ml, about 2050 ng·h / ml, about 2100 ng·h / ml, about 2125 ng·h / ml, about 2150 ng·h / ml, about 2175 ng·h / ml, about 2200 ng·h / ml, about 2225 ng·h / ml, about 2250 ng·h / ml, about 2275 ng·h / ml, about 2300 ng·h / ml, about 2325 ng·h / ml, about 2550 ng·h / ml, about 2575 ng·h / ml, about 2600 ng·h / ml, about 2625 ng·h / ml, about 2650 ng·h / ml, about 2675 ng·h / ml, about 2700 ng·h / ml, about 2725 ng·h / ml, about 2750 ng·h / ml, about 2775 ng·h / ml, about 2800 ng·h / ml, about 2825 ng·h / ml, about 2850 ng·h / ml, about 2875 ng·h / ml, about 2900 ng·h / ml, about 2925 ng·h / ml, or about 2950 ng·h / ml.

[0134] In some embodiments, a method for treating multiple myeloma comprises administering to a patient in need of treatment for multiple myeloma 200 mg per day of niraparstat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt). For example, the method can comprise administering 100 mg of niraparstat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) twice a day. In some embodiments, a method for treating multiple myeloma comprises administering to a patient in need of treatment 100 mg per day of niraparstat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt). In some embodiments, a method for treating multiple myeloma comprises administering to a patient in need of treatment 100 mg per day of niraparstat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt). In some embodiments, a method for treating multiple myeloma comprises administering to a patient in need of treatment 50 mg per day of niraparstat or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt).

[0135] In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) that exceeds 100 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 150 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 200 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 250 ng / ml to about 500 ng / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral formulation of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide form), wherein the oral formulation results in an average maximum drug plasma concentration (C max ) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml.

[0136] In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide salt form), wherein the oral dose results in an average maximum drug plasma concentration (C max ) that exceeds 225 ng / ml. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide salt form), wherein the oral dose results in an average maximum drug plasma concentration (C max ) of about 250 ng / ml to about 750 ng / ml. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide salt form), wherein the oral dose results in an average maximum drug plasma concentration (C max ) of about 300 ng / ml to about 750 ng / ml. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in hydrobromide salt form), wherein the oral dose results in an average maximum drug plasma concentration (C max) results in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage form results in an average maximum drug plasma concentration (C max ) of about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, about 500 ng / ml, about 525 ng / ml, about 550 ng / ml, about 575 ng / ml, about 600 ng / ml, about 625 ng / ml, about 650 ng / ml, about 675 ng / ml, about 700 ng / ml, about 725 ng / ml, or about 750 ng / ml.

[0137] In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf ) of less than 700 ng·h / ml. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf ) of about 200 ng·h / ml to about 650 ng·h / ml. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage form of 50 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC) of about 200 ng·h / ml, about 225 ng·h / ml, about 250 ng·h / ml, about 275 ng·h / ml, about 300 ng·h / ml, about 325 ng·h / ml, about 350 ng·h / ml, about 375 ng·h / ml, about 400 ng·h / ml, about 425 ng·h / ml, about 450 ng·h / ml, about 475 ng·h / ml, about 500 ng·h / ml, about 525 ng·h / ml, about 550 ng·h / ml, about 575 ng·h / ml, about 600 ng·h / ml, about 625 ng·h / ml, or about 675 ng·h / ml inf ) results in.

[0138] In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC inf ) that is less than 3000 ng·h / ml. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC) of about 200 ng·h / ml to about 2950 ng·h / ml inf)resulting. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dose results in a plasma area under the curve (AUC inf) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method of treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf)resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC inf )resulting. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the in vivo plasma curve (AUC inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage results in a plasma area under the curve (AUC inf)resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide salt form), wherein the oral formulation results in a plasma area under the curve (AUC inf) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf ) results in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral formulation of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral formulation results in a plasma area under the curve (AUC inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dose of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in a plasma area under the curve (AUC inf) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient a 100 mg oral dose of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the plasma curve (AUC) in vivo of about 2300 ng·h / ml to about 2950 ng·h / ml inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient a 100 mg oral dose of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the plasma curve (AUC) in vivo of about 2350 ng·h / ml to about 2950 ng·h / ml inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient a 100 mg oral dose of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the plasma curve (AUC) in vivo of about 2400 ng·h / ml to about 2950 ng·h / ml inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient a 100 mg oral dose of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the plasma curve (AUC) in vivo of about 2450 ng·h / ml to about 2950 ng·h / ml inf ) that results. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient a 100 mg oral dose of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dose results in an area under the plasma curve (AUC) in vivo of about 2500 ng·h / ml to about 2950 ng·h / ml inf)resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf )resulting in. In some embodiments, in a patient in need of treating multiple myeloma, a method for treating multiple myeloma comprises administering to the patient an oral dosage of 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide salt form), wherein the oral dosage results in an area under the plasma curve (AUC inf) results. In some embodiments, in a patient in need of treatment for multiple myeloma, a method for treating multiple myeloma comprises administering to the patient a 100 mg oral dosage form of niraparib or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form), wherein the oral dosage provides an area under the plasma concentration-time curve (AUC) of from about 200 ng·h / ml, about 225 ng·h / ml, about 250 ng·h / ml, about 275 ng·h / ml, about 300 ng·h / ml, about 325 ng·h / ml, about 350 ng·h / ml, about 375 ng·h / ml, about 400 ng·h / ml, about 425 ng·h / ml, about 450 ng·h / ml, about 475 ng·h / ml, about 500 ng·h / ml, about 525 ng·h / ml, about 550 ng·h / ml, about 575 ng·h / ml, about 600 ng·h / ml, about 625 ng·h / ml, about 675 ng·h / ml, about 700 ng·h / ml, about 725 ng·h / ml, about 750 ng·h / ml, about 775 ng·h / ml, about 800 ng·h / ml, about 825 ng·h / ml, about 850 ng·h / ml, about 875 ng·h / ml, about 900 ng·h / ml, about 925 ng·h / ml, about 950 ng·h / ml, about 975 ng·h / ml, about 1000 ng·h / ml, about 1025 ng·h / ml, about 1050 ng·h / ml, about 1075 ng·h / ml, about 1100 ng·h / ml, about 1125 ng·h / ml, about 1150 ng·h / ml, about 1175 ng·h / ml, about 1200 ng·h / ml, about 1225 ng·h / ml, about 1250 ng·h / ml, about 1275 ng·h / ml, about 1300 ng·h / ml, about 1325 ng·h / ml, about 1350 ng·h / ml, about 1375 ng·h / ml, about 1400 ng·h / ml, about 1425 ng·h / ml, about 1450 ng·h / ml, about 1475 ng·h / ml, about 1500 ng·h / ml, about 1525 ng·h / ml, about 1550 ng·h / ml, about 1575 ng·h / ml, about 1600 ng·h / ml, about 1625 ng·h / ml, about 1650 ng·h / ml, about 1675 ng·h / ml, about 1700 ng·h / ml, about 1725 ng·h / ml, about 1750 ng·h / ml, about 1775 ng·h / ml, about 1800 ng·h / ml, about 1825 ng·h / ml, about 1850 ng·h / ml, about 1875 ng·h / ml, about 1900 ng·h / ml, about 1925 ng·h / ml,Approximately 1950 ng·h / ml, approximately 2000 ng·h / ml, approximately 2025 ng·h / ml, approximately 2050 ng·h / ml, approximately 2100 ng·h / ml, approximately 2125 ng·h / ml, approximately 2150 ng·h / ml, approximately 2175 ng·h / ml, approximately 2200 ng·h / ml, approximately 2225 ng·h / ml, approximately 2250 ng·h / ml, approximately 2275 ng·h / ml, approximately 2300 ng·h / ml, approximately 2325 ng·h / ml, approximately 2550 ng·h / ml, approximately 2575 ng·h / m, l, approximately 2600 ng·h / ml, approximately 2625 ng·h / ml, approximately 2650 ng·h / ml, approximately 2675 ng·h / ml, approximately 2700 ng·h / ml, approximately 2725 ng·h / ml, approximately 2750 ng·h / ml, approximately 2775 ng·h / ml, approximately 2800 ng·h / ml, approximately 2825 ng·h / ml, approximately 2850 ng·h / ml, approximately 2875 ng·h / ml, approximately 2900 ng·h / ml, approximately 2925 ng·h / ml, or approximately 2950 ng·h / ml of the area under the plasma curve (AUC inf ) is provided.

[0139] In some embodiments, a method for treating multiple myeloma comprises orally administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form). In some embodiments, a method for treating multiple myeloma comprises orally administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form) as a solid dosage form. In some embodiments, the solid dosage form is a tablet or a capsule.

[0140] In some embodiments, a method for treating multiple myeloma comprises administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) once daily. In some embodiments, a method for treating multiple myeloma comprises administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) twice daily. In some embodiments, a method for treating multiple myeloma comprises administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) two, three, or four times daily. When nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) is administered multiple times a day, the total daily dose administered each time may be the same or different. For example, when 100 mg of nilotinib or a pharmaceutically acceptable salt thereof (e.g., in the form of the dihydrobromide salt) is administered twice daily, the patient may receive a 50 mg dose twice (e.g., a 50 mg dose at 8:00 am and a 50 mg dose at 8:00 pm), or a 25 mg dose once in the morning and a 75 mg dose once in the evening. Each administration may be composed of multiple solid dosage forms. For example, an individual dose of 50 mg (i.e., the morning dose of the total daily dose of 100 mg administered in two divided doses) can be administered as two 25 mg tablets.

[0141] In some embodiments, a method for treating multiple myeloma comprises administering a single oral dose of niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) for combination therapy of multiple myeloma. In combination therapy for treating multiple myeloma, niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) is administered with one or more additional active ingredients. In some embodiments, combination therapy for treating multiple myeloma comprises administering niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) in combination with BCMA therapy. In some embodiments, BCMA-targeted therapy comprises one or more of chimeric antigen receptor T cell (CAR-T) therapy, autologous chimeric antigen receptor T cell therapy, immunotherapy (e.g., monoclonal antibody therapy), antibody-drug conjugate therapy, or bispecific antibody therapy having bispecificity for BCMA and an immune-related target (e.g., CD3). In other embodiments, BCMA-targeted therapy comprises at least chimeric antigen receptor T cell therapy. In other embodiments, BCMA-targeted therapy comprises at least autologous chimeric antigen receptor T cell therapy. In another embodiment, BCMA-targeted therapy comprises at least immunotherapy (e.g., monoclonal antibody therapy). In other embodiments, BCMA-targeted therapy comprises at least antibody-drug conjugate therapy. In other embodiments, BCMA-targeted therapy comprises at least bispecific antibody therapy having bispecificity for BCMA and an immune-related target (e.g., CD3). In some embodiments, a method for treating multiple myeloma comprises administering to a patient an oral dose of niraparstat or a pharmaceutically acceptable salt thereof in combination with belantamab mafodotin.

[0142] In combination therapy for treating multiple myeloma (e.g., in combination with belantamab mafodotin), niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) is administered to a subject before, at the same time as, or after one or more other active ingredient(s) (e.g., belantamab mafodotin).

[0143] In some embodiments, treating multiple myeloma involves, as a first-line therapy, a combination therapy of nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form) and one or more other active ingredients (e.g., belantamab mafodotin). In such embodiments, a patient with multiple myeloma may have previously had and / or may currently be receiving treatment for one or more unrelated diseases or disorders (e.g., anxiety).

[0144] In some embodiments, treating multiple myeloma involves administering nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form) and a BCMA-targeted therapy (e.g., belantamab mafodotin) to a patient who has previously received treatment for multiple myeloma. In some embodiments, a patient with multiple myeloma has previously received treatment for multiple myeloma by one or more of a proteasome inhibitor, immunomodulatory therapy, immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody directed against CD38), stem cell transplantation, chemotherapy, targeted therapy (e.g., an XPO1 inhibitor), or a BCMA-targeted therapy not in combination with nilotinib.

[0145] In one embodiment, nilotinib or a pharmaceutically acceptable salt thereof (e.g., the dihydrobromide form) is administered orally to a subject, and a BCMA-targeted therapy (e.g., belantamab mafodotin) is administered intravenously or subcutaneously.

[0146] In some embodiments, patients with multiple myeloma exhibit a complete response after administration of niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) and a therapy targeting BCMA (e.g., belantamab mafodotin). In some embodiments, patients with multiple myeloma exhibit a near-complete response after administration of niraparstat or a pharmaceutically acceptable salt thereof and a therapy targeting BCMA (e.g., belantamab mafodotin). In some embodiments, patients with multiple myeloma exhibit a stringent complete response after administration of niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) and a therapy targeting BCMA (e.g., belantamab mafodotin). In some embodiments, patients with multiple myeloma exhibit a minor response after administration of niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) and a therapy targeting BCMA (e.g., belantamab mafodotin). In some embodiments, patients with multiple myeloma exhibit a partial response after administration of niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) and a therapy targeting BCMA (e.g., belantamab mafodotin). In some embodiments, patients with multiple myeloma exhibit a best partial response after administration of niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) and a therapy targeting BCMA (e.g., belantamab mafodotin). In some embodiments, patients with multiple myeloma exhibit stable disease after administration of niraparstat or a pharmaceutically acceptable salt thereof (e.g., the hydrobromide form) and a therapy targeting BCMA (e.g., belantamab mafodotin).

[0147] Examples Example 1: Pharmacokinetics The pharmacokinetic parameters of a single oral dose of niraparstat hydrobromide (PF-03084014) are shown in Tables 2A-2D below. [Table 2] [Table 3]

Table 4

Table 5

[0148] The pharmacokinetic parameters when nilogacestat dihydrobromide (150 mg, free base equivalent dose) was orally administered twice a day at steady-state exposure are shown in Table 2E below.

Table 6

[0149] Example 2: A randomized, double-blind, placebo-controlled Phase 3 trial of nilogacestat versus placebo in adult patients with progressive desmoid tumor / aggressive fibromatosis (DT / AF) A phase 3, double-blind, placebo-controlled trial was conducted to determine the efficacy and safety of nilotinib hydrobromide in participants with progressive desmoid tumors. Preliminary efficacy was shown in a phase 1 solid tumor trial (Messersmith, W., et al., “A Phase I, dose-finding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014” Clin. Cancer Res., 21:60-7 (2015)), which included long-term durable responses and safety of nilotinib in desmoid participants (Villalobos, V.M., et al., “Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor, Ann. Surg. Oncol., 25:768-75 (2018)). These promising results led to a phase 2 trial in participants with progressive desmoid tumors (Kummar, S., et al., “Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults with Desmoid Tumors (Aggressive Fibromatosis), J. Clin. Oncol., 35:1561-69 (2017)). This trial demonstrated a 29% response rate with nilotinib, with tumors significantly shrinking as measured by magnetic resonance imaging (MRI), and no participants progressing during treatment. Importantly, participants in the response group had not responded to previous systemic therapies (imatinib or sorafenib), indicating that this patient population requires alternative treatment options. These results support further testing of nilotinib in this population.

[0150] The objectives and endpoints are shown in Table 3.

Table 7

[0151] Overall Design: The Phase 3 trial is a multi-site, randomized, double-blind, placebo-controlled, event-driven trial to compare the efficacy, safety, and tolerability of nilogicstat and placebo in adult participants with progressive DT / AF. This trial consists of two phases: a double-blind phase and an optional open-label extension (OLE) phase.

[0152] After disease progression (confirmed by central review using RECIST v1.1) or completion of the double-blind phase (after the required number of events have been observed and the primary PFS analysis has been completed), the treatment assignment of participants is unblinded, and eligible participants have the option to enroll in the optional OLE phase.

[0153] Participant Types and Disease Characteristics: 1. Participants have DT / AF that has progressed by 20% as measured by RECIST v1.1 during the 12 months prior to the first dose of investigational treatment. 2. Participants have: a. Newly diagnosed, measurable, progressive DT / AF for which surgical resection or radiation therapy is not indicated; or b. DT / AF that recurs and progresses after CR to initial therapy; or c. Existing DT / AF that has been previously treated and has residual tumor progression. 3. Participants agree to provide archived or new tumor tissue for disease confirmation. 4. If a participant has previously received investigational therapy for the treatment of DT / AF, the participant must have completed the previous treatment at least 28 days prior to signing the informed consent. All toxicities from the previous therapy must have resolved to Grade 1 or less or to baseline. 5. As a treatment for conditions other than DT / AF, participants receiving non-steroidal anti-inflammatory drugs (NSAIDs) must have been administered NSAIDs as follows (Eligibility Criterion 1) before the following progression is observed: a. Chronic daily regular use (defined as stable for 28 days prior to signing the informed consent); or b. Occasional use (defined as ≤ 3 days per week) as an analgesic or anti-inflammatory agent for approved symptoms such as headache, arthritis, etc. c. The participant has an ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2 at screening. 6. Participants must have appropriate organ and bone marrow function as defined by the following screening test values: a. Absolute neutrophil count ≥ 1500 / μL; b. Platelets ≥ 100×10 3 / μL; c. Hemoglobin ≥ 9 g / dL; d. Total bilirubin ≤ 1.5 × upper limit of normal range (ULN) (if bilirubin is fractionated and direct bilirubin is < 35%, a separated bilirubin > 1.5 × ULN is acceptable); e. Aspartate aminotransferase (AST) (serum glutamate oxaloacetate transaminase) / Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase) ≤ 2 × ULN; and f. Creatinine ≤ 1.5 × ULN, or if creatinine > 1.5 × ULN, the calculated creatinine clearance must be ≥ 60 mL / min / 1.73 m 2 (using the Cockcroft-Gault formula); g. The participant can swallow tablets and does not have a gastrointestinal condition that affects absorption.

[0154] A schematic diagram of this Phase 3 clinical trial is shown in Figure 1.

[0155] Trial Treatment Participants received either (1) three 50 mg nilogersstat tablets twice daily (i.e., 150 mg of nilogersstat twice daily for a total daily dose of 300 mg of nilogersstat), or (2) three placebo tablets twice daily. Nilogersstat in the tablets was in the form of its dihydrobromide salt.

[0156] Due to the inhibition of the CYP3A4 isoenzyme, which can increase the exposure of nilogersstat and lead to a potential increase in toxicity, the use of known strong / moderate CYP3A4 inhibitors was not permitted. Nilogersstat metabolism can be induced when taking strong CYP3A4 inducers, which can result in a decrease in plasma concentration. Therefore, concomitant administration of nilogersstat and strong CYP3A4 inducers was not allowed.

[0157] The co-administration of gastric acid secretion inhibitors such as proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, etc.) can reduce the absorption of nilogersstat. Administration of these drugs should be avoided as much as possible, or, if necessary, administered 2 - 4 hours after the morning dose of the investigational treatment.

[0158] The dose was changed or interrupted as described in the following table.

Table 8

[0159] The most frequently occurring adverse reactions that required dose reduction or interruption were diarrhea, maculopapular rash, hypophosphatemia, stomatitis, folliculitis, and fatigue.

[0160] In this trial, in terms of the improvement in progression-free survival (PFS), the primary endpoint, nilogacestat showed a statistically and clinically significant improvement over placebo, significantly reducing the risk of disease progression (p<0.001, hazard ratio (HR)=0.29). In addition to achieving the primary endpoint, in this trial, nilogacestat showed statistically significant improvements in objective response rate (ORR), four different quality of life (QoL) assessments, and patient-reported outcomes (PRO) (p<0.001 for each), and all major secondary endpoints were also achieved. The data are shown in Figures 3 to 8. The description of the clinical trial and results is also described in Gounder et al., N Engl J Med 2023, 388:898-912 (DOI: 10.1056 / NEJMoa2210140), the entire content of which is incorporated herein by reference.

[0161] The primary outcome measure was the number of progression-free survival events defined as the time from randomization to the date of assessment of progression or death. The major secondary and exploratory endpoints included the following. Incidence of adverse events due to toxicity graded according to the National Cancer Institute's "Common Terminology Criteria for Adverse Events", ORR according to RECIST 1.1 criteria, duration of response (not included in the trial strata) of participants with best response of CR or PR, change in tumor volume from baseline measured by MRI (exploratory). The PRO assessments included the Gounder / Desmoid Tumor Research Foundation (DTRF) Desmoid Symptom / Impact Scale (GODDESS bacteremia) (period: the last 7 days of each cycle (28 days / cycle), daily until the end of the trial), BPI short form (the last 7 days of each cycle, daily), PROMIS PF short form + 3 additional items a (the last day of each cycle), and EORTC QLQ-C30 (the last day of each cycle).

[0162] Table 4 shows the mean change from baseline in the EORTC.

Table 9

[0163] Example 3: A placebo-controlled Phase 3 trial of nilogacestat in adults with progressive desmoid tumor / aggressive fibromatosis (DT / AF) In adult participants with uncontrolled pain due to DT / AF, a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial is conducted to compare the efficacy, safety, and tolerability of nilogacestat and placebo. This trial consists of two phases for eligible participants: a double-blind phase and an optional open-label extension (OLE) phase.

[0164] Participants are screened up to 28 days before the first dose of investigational treatment, and eligibility is determined based on inclusion and exclusion criteria. During the screening period, potential participants are screened for their willingness to record a daily diary of pain and medication use over a 12-week period.

[0165] During the screening period, participants are required to record pain and analgesic use daily. This record is used to calculate the weekly average pain intensity (API) and average analgesic use (AAU). Only participants with uncontrolled tumor-related pain for at least two consecutive weeks (defined as API > 4) are randomly assigned to this trial.

[0166] Eligible participants will be randomized (1:1) to receive investigational treatment (nilogersstat or placebo) after all pre-randomization / pre-dose evaluations are conducted on Day 1 of Cycle 1. After receiving the first dose of investigational treatment, participants will return to the clinic for scheduled study visits at Cycle 1 (Day 15), Cycle 2 (Days 1 and 15), Cycle 3 (Days 1 and 15), End of Study (EOS) (14 days after Day 15 of Cycle 3), and Follow-up (30 days after the last dose of investigational treatment if the participant does not enter the OLE phase).

[0167] During the 12-week investigational treatment period, participants are required to record their daily pain scores, analgesic use, and investigational treatment doses on an electronic device (eDiary). Daily reminders will be sent via electronic means and / or telephone to ensure strict compliance with the data collection procedures for pain and medication use. During the scheduled study clinic visits, the participant's daily pain scores and medication lists will be verified. Additionally, the "EQ-5D" (European Quality of Life Five Dimension), "EORTC QLQ-C30" (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire), "PGI-C" (Patient Global Impression of Change), "PGI-S" (Patient Global Impression of Severity), and "BPI-SF" (Brief Pain Inventory (Short Form)) will be administered to collect health status data.

[0168] After the completion of the trial, participants will return to the facility for the EOS visit (approximately 14 days after Day 15 of Cycle 3). During the EOS visit, eligible participants will have the option to enroll in any OLE phase.

[0169] Participants who discontinue the investigational treatment permanently for any reason must return to the investigational site as soon as possible, as close as possible to the time before the discontinuation of the investigational treatment or the last administration of the investigational treatment, and complete the end of treatment ("EOT") visit. These participants are not eligible to enroll in any OLE phase.

[0170] A schematic diagram of this Phase 3 clinical trial is shown in Figure 2.

[0171] Example 4: Multiple Myeloma The purpose of this study is to evaluate the safety and efficacy of niraparstat in combination with agents targeting B-cell maturation antigen (BCMA), such as antibody-drug conjugates (ADCs), bispecific antibodies, CAR-T therapies, or monoclonal antibodies, in adults with relapsed or refractory multiple myeloma.

[0172] Measurable endpoints may include the following: ● DE phase: The number of participants who achieved an ORR (ORR is defined as the proportion of participants with a PR or better according to the response criteria of the International Myeloma Working Group "IMWG"). ● CE phase: The number of participants who achieved a clinical benefit rate (CBR) (CBR is defined as the proportion of participants with advanced or metastatic cancer who achieved a complete response, partial response, or stable disease to a treatment intervention in a clinical trial of anticancer agents). ● DE phase and CE phase: The number of participants who achieved a partial response ("PR"): Analyze the number of participants who achieved a PR according to the IMWG criteria. ● DE phase and CE phase: The number of participants who achieved a very good partial response ("VGPR"): Analyze the number of participants who achieved a VGPR according to the IMWG criteria. ● DE phase and CE phase: The number of participants who achieved a complete response (CR): Analyze the number of participants who achieved a CR according to the IMWG criteria. ● DE phase and CE phase: The concentration of niraparstat when administered in combination with a second agent: Collect blood samples for the concentration of niraparstat. ●CE phase: The number of participants who achieved progression-free survival (PFS) (PFS is defined as the period from randomization to the earliest date of progressive disease (PD) confirmed by IMWG, or death for any reason). ●CE phase: Duration of response (DoR) (DoR is defined as the time from the first recorded evidence of partial response or greater response achieved by a participant to disease progression or death due to disease progression as determined by IMWG in participants who achieved confirmed partial response or greater response). ●CE phase: Time to response (TTR) (TTR is defined as the time between the date of randomization and the first recorded evidence of response (PR or greater) in participants who achieved response (PR or greater was confirmed)). ●CE phase: The number of participants who achieved overall survival (OS) (OS is defined as the time from randomization to death for any reason).

[0173] Additional endpoints may include the following; ●Overall response rate (ORR) (ORR is defined as the proportion of participants who achieved partial response (PR) or greater according to the IMWG 2016 criteria). ●Very good partial response (VGPR) or greater response rate (VGPR or greater response rate is defined as the proportion of participants who achieved VGPR or greater response (stringent complete response (“sCR”) + complete response (“CR”) + VGPR) according to the IMWG 2016 criteria). ●Complete response (CR) or greater response rate (CR or greater response rate is defined as the proportion of participants who achieved CR or greater response (sCR + CR) according to the IMWG 2016 criteria). ●Stringent complete response (sCR) rate (sCR rate is defined as the proportion of participants who achieved sCR according to the IMWG 2016 criteria). ●Duration of response (Duration of response is defined as the period from the first recorded date of response (PR or greater) to the first recorded evidence of progressive disease (PD) according to the IMWG 2016 criteria). ● Time to efficacy (time to efficacy is defined as the time from the first administration date of the investigational treatment to the first efficacy assessment in which the participant met all criteria of PR or better).

[0174] Eligibility criteria may include the following: ● A diagnosis of relapsed / refractory multiple myeloma ("MM") is recorded and has measurable lesions (serum, urine, or free light chain ("FLC")) as measured according to the IMWG criteria. ● Received at least 3 lines of MM therapies such as proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies (unless contraindicated) and is refractory to the last line of treatment. ● "ECOG" (Eastern Cooperative Oncology Group) 0 or 1 ● Absence of donor (product)-specific anti-HLA antibodies ● Participants with an ECOG performance status of 0 to 1, except when the cause of an ECOG of 2 or less is only skeletal complications and / or skeletal pain due to MM. ● Participants with measurable disease defined as at least one of the following: serum M protein of 0.5 grams / deciliter or more (5 grams / liter or more), or urine M protein of 200 mg or more per 24 hours, or serum free light chain ("FLC") assay: the FLC level involved is 10 mg / deciliter or more (100 mg / liter or more) and an abnormal serum FLC ratio (<0.26 or >1.65).

[0175] All publications, patents, and patent applications described in this specification are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. If a term in this application is found to have a different definition in a document incorporated by reference into this specification, the definition set forth in this specification shall function as the definition of that term.

[0176] Although the present invention has been described with its specific embodiments, it will be understood that further modifications are possible. Also, this application is intended to cover any variations, uses, or adaptations of the present disclosure, including departures from the present disclosure that come within the scope of the claims and that fall within the known or customary practice within the technical field to which the invention pertains, generally following the principles and being within the essential features shown above.

Claims

1. A method for treating desmoid tumors in a patient in need thereof, comprising orally administering nilotinib or a pharmaceutically acceptable salt thereof to the patient twice daily at a dose of 150 mg (free base equivalent dose), wherein (a) for a patient in whom grade 3 diarrhea persists for at least 3 days despite maximal medical therapy, the nilotinib or a pharmaceutically acceptable salt thereof is discontinued until the diarrhea resolves to grade 1 or less diarrhea or returns to baseline, and thereafter, oral administration of the composition is resumed at a dose of 100 mg (free base equivalent dose) twice daily; (b) for a patient having grade 3 folliculitis, the nilotinib or a pharmaceutically acceptable salt thereof is discontinued until the folliculitis resolves to grade 1 or less folliculitis or returns to baseline, and thereafter, oral administration of the nilotinib or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice daily; (c) for a patient having grade 3 macular papular rash, the nilotinib or a pharmaceutically acceptable salt thereof is discontinued until the macular papular rash resolves to grade 1 or less macular papular rash or returns to baseline, and thereafter, oral administration of the nilotinib or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice daily; (d) for a patient having grade 3 hidradenitis, the nilotinib or a pharmaceutically acceptable salt thereof is discontinued until the hidradenitis resolves to grade 1 or less hidradenitis or returns to baseline, and thereafter, oral administration of the nilotinib or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice daily; (e) for a patient in whom grade 3 hypophosphatemia persists for at least 7 days despite maximal replacement therapy, the nilotinib or a pharmaceutically acceptable salt thereof is discontinued until the hypophosphatemia resolves to grade 1 or less hypophosphatemia or returns to baseline, and thereafter, oral administration of the nilotinib or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice daily; (f) Notwithstanding maximum replacement therapy, for the patient having grade 3 hypokalemia, discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the hypokalemia is grade 1 or lower hypokalemia or has recovered to baseline, and then restarting oral administration of the nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (g) For the patient having alanine transaminase (ALT) or aspartate aminotransferase (AST) that is 3 to 5 times the upper limit of the reference range (ULN), discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the ALT, the AST, or both are 3 times or lower the ULN or have recovered to baseline, and then restarting oral administration of nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, the method comprising one or more of the above. (Claim 2) (The method according to claim 1, further comprising (h) Permanently discontinuing treatment with the nilogersstat or a pharmaceutically acceptable salt thereof for the patient having ALT or AST exceeding 5 times the ULN (i) Permanently discontinuing treatment with the nilogersstat or a pharmaceutically acceptable salt thereof for the patient having anaphylaxis or other severe allergic reaction, and (j) In the case of another severe adverse reaction or a life-threatening adverse reaction, discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the adverse reaction is grade 1 or lower adverse reaction or has recovered to baseline, and then, after carefully considering the potential benefit and the likelihood of recurrence of the adverse reaction, (A) restarting oral administration of the nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, (B) if the severe or life-threatening adverse reaction recurs at the dose of 100 mg (free base equivalent dose) twice daily, permanently discontinuing treatment with the nilogersstat or a pharmaceutically acceptable salt thereof, the method comprising one or more of the above. (Claim 3) The method according to claim 1 or claim 2, comprising: (a) for the patient in whom grade 3 diarrhea persists for at least 3 days despite maximum medical treatment, withholding the nilotinib or a pharmaceutically acceptable salt thereof until the diarrhea recovers to grade 1 or lower diarrhea or baseline, and then restarting oral administration of the nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day.

4. The method according to any one of the preceding claims, comprising: (b) for the patient having grade 3 folliculitis, withholding the nilotinib or a pharmaceutically acceptable salt thereof until the folliculitis recovers to grade 1 or lower folliculitis or baseline, and then restarting oral administration of the nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day.

5. The method according to any one of the preceding claims, comprising: (c) for the patient having grade 3 maculopapular rash, withholding the nilotinib or a pharmaceutically acceptable salt thereof until the maculopapular rash recovers to grade 1 or lower maculopapular rash or baseline, and then restarting oral administration of the nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day.

6. The method according to any one of the preceding claims, comprising: (d) for the patient having grade 3 hidradenitis, withholding the nilotinib or a pharmaceutically acceptable salt thereof until the hidradenitis recovers to grade 1 or lower hidradenitis or baseline, and then restarting oral administration of the nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day.

7. The method according to any one of the preceding claims, wherein (e) for the patient in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, the nilugacetstat or a pharmaceutically acceptable salt thereof is discontinued until the hypophosphatemia recovers to grade 1 or lower hypophosphatemia or baseline, and thereafter, oral administration of the nilugacetstat or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice a day.

8. The method according to any one of the preceding claims, wherein (f) for the patient having grade 3 hypokalemia despite maximum replacement therapy, the nilugacetstat or a pharmaceutically acceptable salt thereof is discontinued until the hypokalemia recovers to grade 1 or lower hypokalemia or baseline, and thereafter, oral administration of the nilugacetstat or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice a day.

9. The method according to any one of the preceding claims, wherein (g) for the patient having ALT or AST that is 3 to 5 times the ULN, the nilugacetstat or a pharmaceutically acceptable salt thereof is discontinued until the ALT, AST, or both recover to 3 times the ULN or lower or baseline, and thereafter, oral administration of the nilugacetstat or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice a day.

10. The method according to any one of the preceding claims, wherein (h) for the patient having ALT or AST exceeding 5 times the ULN, treatment with the nilugacetstat or a pharmaceutically acceptable salt thereof is permanently discontinued.

11. The method according to any one of the preceding claims, wherein (i) for the patient having anaphylaxis or other severe allergic reactions, treatment with the nilugacetstat or a pharmaceutically acceptable salt thereof is permanently discontinued.

12. The method is (a) For the patient with grade 3 diarrhea that has persisted for at least 3 days despite maximum medical treatment, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the diarrhea has recovered to grade 1 or less diarrhea or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (b) For the patient with grade 3 folliculitis, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the folliculitis has recovered to grade 1 or less folliculitis or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (c) For the patient with grade 3 maculopapular rash, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the maculopapular rash has recovered to grade 1 or less maculopapular rash or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (d) For the patient with grade 3 hidradenitis, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the hidradenitis has recovered to grade 1 or less hidradenitis or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (e) For the patient with grade 3 hypophosphatemia that has persisted for at least 7 days despite maximum replacement therapy, discontinue nilotinib or a pharmaceutically acceptable salt thereof until the hypophosphatemia has recovered to grade 1 or less hypophosphatemia or baseline, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily. (f) Notwithstanding maximum replacement therapy, for the patient with grade 3 hypokalemia, discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the hypokalemia has recovered to grade 1 or lower hypokalemia or to baseline, and then restarting oral administration of the nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (g) For the patient having ALT or AST that is 3 to 5 times the ULN, discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the ALT, AST, or both have recovered to 3 times the ULN or lower or to baseline, and then restarting oral administration of the nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, the method according to any one of the preceding claims. (Claim 13) The method comprises: (a) Notwithstanding maximum medical treatment, for the patient with grade 3 diarrhea that has persisted for at least 3 days, discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the diarrhea has recovered to grade 1 or lower diarrhea or to baseline, and then restarting oral administration of the nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, (b) For the patient with grade 3 folliculitis, discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the folliculitis has recovered to grade 1 or lower folliculitis or to baseline, and then restarting oral administration of the nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, (c) For the patient with grade 3 maculopapular rash, discontinuing the nilogersstat or a pharmaceutically acceptable salt thereof until the maculopapular rash has recovered to grade 1 or lower maculopapular rash or to baseline, and then restarting oral administration of the nilogersstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, (d) For the patient having hidradenitis grade 3, until the hidradenitis recovers to hidradenitis grade 1 or lower or to the baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and thereafter resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (e) For the patient in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, until the hypophosphatemia recovers to hypophosphatemia grade 1 or lower or to the baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and thereafter resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (f) For the patient having grade 3 hypokalemia despite maximum replacement therapy, until the hypokalemia recovers to hypokalemia grade 1 or lower or to the baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and thereafter resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (g) For the patient having ALT or AST that is 3 to 5 times the ULN, until the ALT, AST, or both of them recover to 3 times the ULN or lower or to the baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and thereafter resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (h) For the patient having ALT or AST exceeding 5 times the ULN, permanently discontinue the treatment with nilotinib or a pharmaceutically acceptable salt thereof. (i) For the patient having anaphylaxis or other severe allergic reactions, permanently discontinue the treatment with nilotinib or a pharmaceutically acceptable salt thereof, and (j) In the case of another severe adverse reaction or a life-threatening adverse reaction, until the adverse reaction is an adverse reaction of grade 1 or lower or has recovered to the baseline, discontinue the nilogasostat or a pharmaceutically acceptable salt thereof, and then, after carefully considering the potential benefit and the possibility of recurrence of the adverse reaction, (A) resume the oral administration of the nilogasostat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day, (B) if the severe or life-threatening adverse reaction recurs at the dose of 100 mg (free base equivalent dose) twice a day, permanently discontinue the treatment with the nilogasostat or a pharmaceutically acceptable salt thereof. The method according to claim 1.

14. For the patient having a grade 3 dermatological reaction, until the dermatological reaction has recovered to a dermatological reaction of grade 1 or lower, discontinue the nilogasostat or a pharmaceutically acceptable salt thereof, and then resume the oral administration of the nilogasostat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. The method according to any one of the preceding claims.

15. The method according to any one of the preceding claims, wherein the patient has a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene.

16. The method according to any one of the preceding claims, wherein the patient has a mutation in the CTNNB1 (β-catenin) gene.

17. The method according to any one of the preceding claims, wherein the patient has a treatment history with a tyrosine kinase inhibitor.

18. The method according to any one of the preceding claims, wherein the patient has an intra-abdominal tumor.

19. The method according to any one of the preceding claims, wherein the patient is an adult.

20. The method according to any one of the preceding claims, wherein the patient has a family history of familial adenomatous polyposis.

21. The method according to any one of the preceding claims, wherein the patient has a refractory or recurrent disease after prior treatment.

22. The method according to any one of the preceding claims, wherein the patient is an untreated patient.

23. The method according to any one of the preceding claims, wherein the patient is a postmenopausal woman.

24. The method according to any one of the preceding claims, wherein the gastric acid reducer is avoided or administered 4 hours after the administration of the nilotinib or a pharmaceutically acceptable salt thereof.

25.

25. A method for treating desmoid tumors in a patient having a family history of familial adenomatous polyposis, comprising orally administering to the patient nilotinib or a pharmaceutically acceptable salt thereof at a dose of 150 mg (free base equivalent dose) twice a day.

26.

26. A method for treating desmoid tumors in an untreated patient, comprising orally administering to the patient nilotinib or a pharmaceutically acceptable salt thereof at a dose of 150 mg (free base equivalent dose) twice a day.

27.

27. The method according to any one of the preceding claims, wherein the nilotinib or a pharmaceutically acceptable salt thereof is nilotinib dihydrobromide.

28. After the first administration of 150 mg (free base equivalent dose) of nilogersat or a pharmaceutically acceptable salt thereof to the patient, the C of nilogersat is about 480 to about 950 ng / mL ｍａｘ The method according to any one of the preceding claims, showing

29. After the first administration of 150 mg (free base equivalent dose) of nilogicstat or a pharmaceutically acceptable salt thereof to the patient, the C of nilogicstat is about 550 to about 1100 ng / mL ｍａｘ The method according to any one of the preceding claims, showing

30. After the first administration of 150 mg (free base equivalent dose) of nilogersstat or a pharmaceutically acceptable salt thereof to the patient, the C of nilogersstat of about 600 to about 800 ng / mL ｍａｘ The method according to claim 29, showing.

31. The method according to any one of the preceding claims, wherein the patient exhibits an AUC of nilotinib less than 4000 ng·h / mL after the first administration of 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof. ｌａｓｔ ​

32. The method according to any one of the preceding claims, wherein the patient has an AUC of nilotinib of about 2000 to about 4000 ng·h / mL after the first administration of 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof. ｌａｓｔ as shown.

33. The method according to any one of the preceding claims, wherein the patient has an AUC of nilotinib of about 2200 to about 4800 ng·h / mL after the first administration of 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof. ｉｎｆ as shown.

34. The method according to claim 33, wherein the patient exhibits an AUC of nilotinib of about 2200 to about 3300 ng·h / mL after the first administration of 150 mg (free base equivalent dose) of nilotinib or a pharmaceutically acceptable salt thereof. ｉｎｆ as shown.

35. In the steady state where the patient has been administered nilotinib at a dose of 150 mg (free base equivalent dose) twice a day or a pharmaceutically acceptable salt thereof, the C of nilotinib ｍａｘ is about 1000 to 1500 ng / mL, the method according to any one of the preceding claims.

36. In the steady state where the patient has been administered nilotinib at a dose of 150 mg (free base equivalent dose) twice a day or a pharmaceutically acceptable salt thereof, the C ｍａｘ of nilotinib is about 1100 to 1400 ng / mL, the method according to claim 35.

37. In the steady state where the patient has been administered nilotansstat at 150 mg (free base equivalent dose) twice a day, the AUC of nilotansstat ｔａｕ is about 5000 to 8000 ng·h / mL, the method according to any one of the preceding claims.

38. In the steady state where the patient has been administered nilotansstat at 150 mg (free base equivalent dose) twice a day or a pharmaceutically acceptable salt thereof, the AUC of nilotansstat ｔａｕ is about 6000 to 7000 ng·h / mL, the method according to claim 37.

39. A method for treating multiple myeloma in a patient in need thereof, comprising simultaneously administering to the patient (i) nilotinib or a pharmaceutically acceptable salt thereof, and (ii) one or more additional active ingredients for the treatment of multiple myeloma, the method comprising: (A) orally administering to the patient nilotinib or a pharmaceutically acceptable salt thereof at a dose of 150 mg (free base equivalent dose) twice a day, and (B) (a) Withholding the nilotinib or a pharmaceutically acceptable salt thereof from the patient with grade 3 diarrhea that has persisted for at least 3 days despite maximal medical treatment until the diarrhea has recovered to grade 1 or less diarrhea or baseline, and then restarting oral administration of the nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (b) Withholding the nilotinib or a pharmaceutically acceptable salt thereof from the patient with grade 3 folliculitis until the folliculitis has recovered to grade 1 or less folliculitis or baseline, and then restarting oral administration of the nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (c) For the patient having grade 3 macular papular rash, until the macular papular rash recovers to grade 1 or lower macular papular rash or baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (d) For the patient having grade 3 hidradenitis, until the hidradenitis recovers to grade 1 or lower hidradenitis or baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (e) For the patient in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, until the hypophosphatemia recovers to grade 1 or lower hypophosphatemia or baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day. (f) For the patient having grade 3 hypokalemia despite maximum replacement therapy, until the hypokalemia recovers to grade 1 or lower hypokalemia or baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day, and (g) For the patient having alanine transaminase (ALT) or aspartate aminotransferase (AST) at 3 to 5 times the upper limit of the reference range (ULN), until the ALT, AST, or both of them recover to 3 times or less the ULN or baseline, discontinue nilotinib or a pharmaceutically acceptable salt thereof, and then resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day, the method comprising one or more of the above.

40. The method according to claim 39, wherein BCMA therapy is co-administered to the patient.

41. The method according to claim 39 or 40, further comprising (h) Permanently discontinuing treatment with said nilotinib or a pharmaceutically acceptable salt thereof for said patient having ALT or AST more than 5 times ULN; (i) Permanently discontinuing treatment with said nilotinib or a pharmaceutically acceptable salt thereof for said patient having anaphylaxis or other severe hypersensitivity reactions; and (j) In the case of another severe adverse reaction or a life-threatening adverse reaction, if the adverse reaction is a grade 1 or lower adverse reaction or until recovery to baseline, withholding said nilotinib or a pharmaceutically acceptable salt thereof, and then, after carefully considering the potential benefit and the likelihood of recurrence of said adverse reaction, (A) resuming oral administration of said nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (B) if the severe or life-threatening adverse reaction recurs at the dose of 100 mg (free base equivalent dose) twice daily, permanently discontinuing treatment with said nilotinib or a pharmaceutically acceptable salt thereof, said method comprising one or more of the above.

42. A method for treating multiple myeloma in a patient in need thereof, comprising simultaneously administering to said patient (i) nilotinib or a pharmaceutically acceptable salt thereof, and (ii) one or more additional active ingredients for the treatment of multiple myeloma, said method comprising (A) orally administering to said patient nilotinib or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily, and (B) (a) Withholding said nilotinib or a pharmaceutically acceptable salt thereof for said patient having grade 3 diarrhea that persists for at least 3 days despite maximum medical treatment until the diarrhea is grade 1 or lower diarrhea or until recovery to baseline, and then resuming oral administration of said nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily; (b) Withholding said nilotinib or a pharmaceutically acceptable salt thereof for said patient having grade 3 folliculitis until the folliculitis is grade 1 or lower folliculitis or until recovery to baseline, and then resuming oral administration of said nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily; (c) For the patient having the grade 3 macular papular rash, until the macular papular rash recovers to a grade 1 or lower macular papular rash or the baseline, discontinue the nilotolisib or a pharmaceutically acceptable salt thereof, and then resume oral administration of the nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 50 mg twice a day (free base equivalent dose). (d) For the patient having the grade 3 hidradenitis, until the hidradenitis recovers to a grade 1 or lower hidradenitis or the baseline, discontinue the nilotolisib or a pharmaceutically acceptable salt thereof, and then resume oral administration of the nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 50 mg twice a day (free base equivalent dose). (e) For the patient in whom grade 3 hypophosphatemia persists for at least 7 days despite maximum replacement therapy, until the hypophosphatemia recovers to a grade 1 or lower hypophosphatemia or the baseline, discontinue the nilotolisib or a pharmaceutically acceptable salt thereof, and then resume oral administration of the nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 50 mg twice a day (free base equivalent dose). (f) For the patient having grade 3 hypokalemia despite maximum replacement therapy, until the hypokalemia recovers to a grade 1 or lower hypokalemia or the baseline, discontinue the nilotolisib or a pharmaceutically acceptable salt thereof, and then resume oral administration of the nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 50 mg twice a day (free base equivalent dose), and (g) For the patient having alanine transaminase (ALT) or aspartate aminotransferase (AST) that is 3 to 5 times the upper limit of the reference range (ULN), until the ALT, AST, or both of them recover to 3 times or less the ULN or the baseline, discontinue the nilotolisib or a pharmaceutically acceptable salt thereof, and then resume oral administration of the nilotolisib or a pharmaceutically acceptable salt thereof at a dose of 50 mg twice a day (free base equivalent dose), the method comprising one or more of the above.

43. The method according to claim 42, wherein BCMA therapy is co-administered to the patient.

44. The method according to claim 42 or 43, further comprising For the patient having ALT or AST exceeding 5 times the upper limit of the reference range (ULN), permanently discontinue treatment with said nilotinib or a pharmaceutically acceptable salt thereof; For the patient having anaphylaxis or other severe hypersensitivity reaction, permanently discontinue treatment with said nilotinib or a pharmaceutically acceptable salt thereof; and In the case of another severe adverse reaction or a life-threatening adverse reaction, if the adverse reaction is a grade 1 or lower adverse reaction or until it recovers to baseline, withhold nilotinib or a pharmaceutically acceptable salt thereof, and then, after carefully considering the potential benefit and the likelihood of recurrence of the adverse reaction, (A) resume oral administration of nilotinib or a pharmaceutically acceptable salt thereof at a dose of 50 mg (free base equivalent dose) twice daily, and (B) if the severe or life-threatening adverse reaction recurs at the dose of 50 mg (free base equivalent dose) twice daily, permanently discontinue treatment with nilotinib or a pharmaceutically acceptable salt thereof, the method comprising one or more of the above.

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