Combination therapy for treating hematological cancers

Abstract

The present disclosure features a combination therapy useful for the treatment of AML and related hematological cancers.

Description

[0001] PATENT

[0002] ATTORNEY DOCKET NO.: 51121-109WO2

[0003] COMBINATION THERAPY FOR TREATING HEMATOLOGICAL CANCERS

[0004] BACKGROUND OF THE INVENTION

[0005] The present disclosure relates to combination therapies including FHD 286 and decitabine for the treatment of AML and related hematological cancers. The combination therapies of the invention can reduce side effects, improve outcomes, and / or reduce the dosing burden on the patient.

[0006] SUMMARY

[0007] The invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

[0008] In another aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (x) an anti-fungal agent or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection, and (y): (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

[0009] In another aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (x) the anti-fungal agent is administered as a (a) a loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (a), administering to the subject (b) a maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (a) the loading dose regimen and (b) the maintenance dose regimen together are effective to reduce the risk of a fungal infection, and wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen, and (y); (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose PATENT

[0010] ATTORNEY DOCKET NO.: 51121-109WO2 regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

[0011] In some embodiments, the method further comprising administering to the subject (iv) an antifungal agent or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection. In some embodiments, wherein (iv) the anti-fungal agent is administered as a (a) a loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (a), administering to the subject (b) a maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (a) the loading dose regimen and (b) the maintenance dose regimen together are effective to reduce the risk of a fungal infection, and wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen.

[0012] In some embodiments, the method further comprising administering to the subject (x) an antifungal agent or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection. In some embodiments, wherein (x) the anti-fungal agent is administered as a (a) a loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (a), administering to the subject (b) a maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (a) the loading dose regimen and (b) the maintenance dose regimen together are effective to reduce the risk of a fungal infection, and wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen.

[0013] In some embodiments, wherein (i) the decitabine is administered at a dose of 15 mg / m2by continuous intravenous transfusion over 3 hours repeated every 8 hours for 3 days. In some embodiments, wherein (i) the decitabine is administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days.

[0014] In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the decitabine is administered (low dose) at a dose of 15 mg / m2by continuous intravenous transfusion over 3 hours repeated every 8 hours for 3 days. In certain embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the decitabine is administered (high dose) at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days.

[0015] In some embodiments of any of the above methods, wherein decitabine, or a pharmaceutically acceptable salt thereof, is administered intravenously. The decitabine cycle is optionally repeated every 4 weeks or every 6 weeks. In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of decitabine. In some embodiments, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, are administered within 24 hours of each other.

[0016] In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically PATENT

[0017] ATTORNEY DOCKET NO.: 51121-109WO2 acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises administering 1 cycle of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments of any of the above methods, the (ii) differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with decitabine for a period of at least one month, two months, three months, or four months. In some embodiments of any of the above methods, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or (iv) anti-fungal agent for a period of at least one month, two months, three months, or four months.

[0019] In some embodiments, wherein (ii) the differentiation dose regimen is sufficient to produce a Caverage plasma concentration level of at least 250 ng / mL in the subject, and the maintenance dose regimen is sufficient to produce a Caverage plasma concentration level of between about 80 ng / mL and about 225 ng / mL in the subject.

[0020] In some embodiments, wherein (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day. In some embodiments, wherein (ii) the differentiation dose regimen comprises administering daily to the subject between about 7.5 mg to 22.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen comprises administering daily to the subject from 1 .5 mg to 7.0 mg of FHD 286, or a pharmaceutically acceptable salt thereof.

[0021] For example, on dosing days (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, can include (1) administering to the subject between about 7.5 mg and about 22.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 7.5 mg and about 10 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 10.0 mg and about 12.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about 12.5 mg and about 15.0 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about 15.0 mg and about 17.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (6) administering to the subject between about 17.5 mg and about 20 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 20 mg and about 22.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (8) administering to the subject between about 20 mg and about 22.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, wherein (ii) the differentiation dose regimen comprising administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to PATENT

[0023] ATTORNEY DOCKET NO.: 51121-109WO2 twenty-eight days. In some embodiments, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days. In some embodiments, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to ten days. In some embodiments, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to five days.

[0024] In some embodiments, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of one day. In some embodiments, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more every ten days to fourteen days. In some embodiments, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more weekly. In some embodiments, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject at least once daily. In some embodiments, wherein (ii) the differentiation dose regimen comprises administering FHD 286, or a pharmaceutically acceptable salt thereof, at an average daily dose of from between about 7.5 mg to 22.5 mg.

[0025] In some embodiments, wherein (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 1 .5 mg per day, about 2.0 mg per day, subject about 2.5 mg per day, about 3.0 mg per day, subject about 3.5 mg per day, about 4.0 mg per day, subject about 4.5 mg per day, about 5.0 mg per day, subject about 5.5 mg per day, about 6.0 mg per day, about 6.5 mg per day, or about 7.0 mg per day. In some embodiments, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more every ten to fourteen days. In some embodiments, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more weekly. In some embodiments, wherein the maintenance dose of FHD 286 is administered to the subject at least once daily.

[0026] For example, on dosing days (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, can include (1) administering to the subject between about 1 .5 mg and about 2.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 2.5 mg and about 5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 5 mg and about 7.0 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof. In some embodiments, wherein (iii) the maintenance dose regimen comprises administering FHD 286, or a pharmaceutically acceptable salt thereof, at an average daily dose of from 1 .0 mg to 7.0 mg.

[0027] In some embodiments, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 2 weeks. In some embodiments, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one month. In some embodiments, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 3 months. In some PATENT

[0028] ATTORNEY DOCKET NO.: 51121-109WO2 embodiments, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least six months. In some embodiments, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 12 months.

[0029] In some embodiments, wherein the ratio of the average daily dose of FHD 286, or a pharmaceutically acceptable salt thereof, administered during (ii) the differentiation dose regimen to the average daily dose of FHD 286, or a pharmaceutically acceptable salt thereof, administered during (iii) the maintenance dose regimen is from 10:1 to 1.25:1.

[0030] In some embodiments, wherein the final dose of (ii) the differentiation dose regimen and the first dose of (iii) the maintenance dose regimen are administered within 1 day of each other. In some embodiments, wherein the final dose of (ii) the differentiation dose regimen and the first dose of the (iii) maintenance dose regimen are administered within 28 days of each other.

[0031] In some embodiments, wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen. In some embodiments, wherein (a) the loading dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least twice daily. In some embodiments, wherein (b) the maintenance dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least once daily. In some embodiments, wherein (a) the loading dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least twice daily, followed by (b) the maintenance dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least once daily.

[0032] In some embodiments, wherein the average daily dose during (a) the loading dose regimen is at least 3-fold higher than the average daily dose during (b) the maintenance dose regimen. In some embodiments, wherein (a) the loading dose regimen comprises administering to the subject about 200 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least three daily. In some embodiments, wherein (b) the maintenance dose regimen comprises administering to the subject about 200 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least once daily. In some embodiments, wherein (a) the loading dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs. In some embodiments, wherein (b) the maintenance dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, wherein (a) the loading dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs, followed by (b) the maintenance dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, wherein (a) the loading dose regimen comprises administering the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at an average daily dose of between about 600 mg to 1200 mg. In some embodiments, wherein (b) the maintenance dose regimen comprises administering FHD 286, or a pharmaceutically acceptable salt thereof, at an average daily dose of between about 200 mg to 400 mg. PATENT

[0033] ATTORNEY DOCKET NO.: 51121-109WO2

[0034] In some embodiments, wherein step (a) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days. In some embodiments, wherein step (a) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 48 hours. In some embodiments, wherein step (b) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days. In some embodiments, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 12 hours of each other. In some embodiments, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 1 day of each other. In some embodiments, wherein the final dose of (a) the loading dose regimen and the first dose of the (b) maintenance dose regimen are administered within 28 days of each other.

[0035] For example, on dosing days (a) the loading dose regimen can include (1) administering to the subject between about 200 mg and about 400 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 200 mg and about 225 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 225 mg and about 250 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about 250 mg and about 275 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about 275 mg and about 300 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (6) administering to the subject between about 300 mg and about 325 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 325 mg and about 350 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (8) administering to the subject between about 350 mg and about 375 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (9) administering to the subject between about 375 mg and about 400 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0036] For example, on dosing days (a) the maintenance dose regimen can include (1) administering to the subject between about 200 mg and about 400 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 200 mg and about 225 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 225 mg and about 250 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about 250 mg and about 275 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about 275 mg and about 300 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (6) PATENT

[0037] ATTORNEY DOCKET NO.: 51121-109WO2 administering to the subject between about 300 mg and about 325 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 325 mg and about 350 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (8) administering to the subject between about 350 mg and about 375 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (9) administering to the subject between about 375 mg and about 400 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments of any of the above methods, wherein (ii) the differentiation dose regimen of FHD 286 is administered orally. In some embodiments of any of the above methods, wherein (iii) the maintenance dose regimen of FHD 286 is administered orally.

[0039] In some embodiments of any of the above methods, wherein (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments of any of the above methods, wherein (x) the antifungal agent, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments of any of the above methods, wherein (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments of any of the above methods, wherein (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein(b) the maintenance dose regimen of the antifungal agent or a pharmaceutically acceptable salt thereof, is intravenously.

[0040] In some embodiments of any of the above methods, wherein the method comprises at least 21 days of treatment. In some embodiments of any of the above methods, wherein the method comprises at least 28 days of treatment.

[0041] In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt and 1 , 2, or 3 cycles of (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable PATENT

[0044] ATTORNEY DOCKET NO.: 51121-109WO2 salt thereof, are administered within 12 hours of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

[0045] In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

[0046] In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

[0047] In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other. In some embodiments of any of the above methods, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other. In some embodiments of any of the above methods, wherein (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the PATENT

[0048] ATTORNEY DOCKET NO.: 51121-109WO2 loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other. In some embodiments of any of the above methods, wherein (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

[0049] In some embodiments of any of the above methods, wherein (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the antifungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other. In some embodiments of any of the above methods, wherein (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (b) the maintenance dose regimen of the antifungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other. In some embodiments of any of the above methods, wherein (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other. In some embodiments of any of the above methods, wherein (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

[0050] In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, without further administering to the subject decitabine, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or PATENT

[0051] ATTORNEY DOCKET NO.: 51121-109WO2 a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject (i) the decitabine, or a pharmaceutically acceptable salt thereof and / or (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein (ii) the differentiation dose regimen is sufficient to induce cell arrest and / or apoptosis in leukemic stem cells in a subject and (iii) the maintenance dose regimen is insufficient to induce cell arrest and / or apoptosis in leukemic stem cells in a subject, but sufficient to reduce the number of blast cells.

[0053] In some embodiments of any of the above methods, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject (i) the decitabine, or a pharmaceutically acceptable salt thereof and / or (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein (ii) the differentiation dose regimen is sufficient to induce cell arrest and / or apoptosis in leukemic stem cells in a subject and (iii) the maintenance dose regimen is insufficient to induce cell arrest and / or apoptosis in leukemic stem cells in a subject, but sufficient to reduce the number of blast cells.

[0054] In another aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (x) the anti-fungal agent is administered as a (c) a low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (c), PATENT

[0055] ATTORNEY DOCKET NO.: 51121-109WO2 administering to the subject (d) a high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (c) the low dose regimen and (d) the high dose regimen together are effective to reduce the risk of a fungal infection, and (y): (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

[0056] In some embodiments, wherein (x) the anti-fungal agent is administered as a (c) a low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (c), administering to the subject (d) a high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (c) the low dose regimen and (d) the high dose regimen together are effective to reduce the risk of a fungal infection. In some embodiments, wherein (iv) the anti-fungal agent is administered as a (c) a low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (c), administering to the subject (d) a high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (c) the low dose regimen and (d) the high dose regimen together are effective to reduce the risk of a fungal infection. In some embodiments, wherein (c) the low dose regimen comprises administering to the subject between about 2.5 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days followed by (d) the high dose regimen comprises administering to the subject about 5.0 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days. In some embodiments, wherein (c) the low dose regimen comprises administering to the subject between about 5.0 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days followed by (d) the high dose regimen comprises administering to the subject about 7.5 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days. In some embodiments, wherein (c) the low dose regimen comprises administering the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at an average daily dose of between about 10 mg to 20 mg. In some embodiments, wherein (d) the high dose regimen comprises administering FHD 286, or a pharmaceutically acceptable salt thereof, at an average daily dose of between about 20 mg to 30 mg.

[0057] In some embodiments, wherein step (c) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days. In some embodiments, wherein step (c) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 48 hours. In some embodiments, wherein step (d) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days. In some embodiments, wherein the final dose of (c) the low dose regimen and the first dose of (d) the high dose regimen are administered within 12 hours of each other. In some embodiments, wherein the final dose of (c) the low dose regimen and the first dose of (d) the high dose regimen are administered within 1 PATENT

[0058] ATTORNEY DOCKET NO.: 51121-109WO2 day of each other. In some embodiments, wherein the final dose of (c) the low dose regimen and the first dose of (d) the high dose regimen are administered within 28 days of each other.

[0059] In some embodiments of any of the above methods, wherein (c) the low dose regimen of an antifungal agent or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein (c) the low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments of any of the above methods, wherein (d) the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein (d) the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered intravenously.

[0060] In some embodiments of any of the above methods, wherein the method comprises administering 1 , 2, or 3 cycles of (c) the low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt and (d) the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof,

[0061] In certain embodiments of any of the above methods, wherein (c) the low dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, comprises administering to the subject a dose of 2.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cycle is performed once, twice, or three times.

[0062] In certain embodiments of any of the above methods, wherein (d) the high dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by a dose of 7.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cycle is performed once, twice, or three times.

[0063] For example, on dosing days the method can include (1) administering to the subject between about 1 .0 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 7.5 mg and about 10 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 5.0 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about 2.5 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about 1 .0 mg and about 5.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (6) administering to the subject between about 1 .0 mg and about 2.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 1 mg and about 7.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (8) administering to the subject between about 5 mg and about 7.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (9) administering to the subject between about PATENT

[0064] ATTORNEY DOCKET NO.: 51121-109WO2

[0065] 2.5 mg and about 7.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (10) administering to the subject about 2.5 mg per day, 5.0 mg per day, about 7.5 mg per day, about 10 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, step (c) includes administering to the subject 2.5 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, step (d) includes administering to the subject 5.0 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, step (c) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days. In some embodiments, step (d) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.

[0068] In some embodiments, the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the FHD 286, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with FHD 286, or one complete treatment cycle of FHD 286 prior to the administration of decitabine, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject the FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject decitabine, or a pharmaceutically acceptable salt thereof. For example, the decitabine treatment can be stopped after one, two, or three cycles of low dose decitabine or high dose decitabine administrations, after which the subject receives additional cycles of FHD 286 therapy.

[0070] In some embodiments, the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the FHD 286, or a pharmaceutically acceptable salt thereof, and / or decitabine, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with FHD 286, and / or decitabine, or one complete treatment cycle of FHD 286 and / or decitabine prior to the administration of the antifungal agent, or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject the FHD 286, or a pharmaceutically acceptable salt thereof, and / or decitabine, or a pharmaceutically acceptable salt thereof, without further administering to the subject anti-fungal agent, or a pharmaceutically acceptable salt thereof. For example, the anti-fungal agent treatment can be stopped after one, two, or three cycles of the low dose regimen of the anti-fungal agent or high dose regimen of the anti-fungal agent administrations, after which the subject receives additional cycles of FHD 286 therapy and / or decitabine.

[0072] In another aspect, the present invention discloses a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (1) isavuconazole, or a pharmaceutically acceptable salt thereof, is administered as a (a) a loading dose regimen of about 200 mg of the isavuconazole or a pharmaceutically acceptable salt thereof, about every 8 hrs for about 48 hrs, PATENT

[0073] ATTORNEY DOCKET NO.: 51121-109WO2 and following step (a), administering to the subject (b) a maintenance dose regimen of about 200 mg of the isavu conazole, or a pharmaceutically acceptable salt thereof, once daily, and (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1.5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

[0074] In another aspect, the present invention discloses a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (1) isavuconazole, or a pharmaceutically acceptable salt thereof, is administered as a (a) a loading dose regimen comprising 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs, and following step (a), administering to the subject (b) a maintenance dose regimen comprising 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, once daily, and (i) decitabine, or a pharmaceutically acceptable salt thereof, administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, which comprises 7.5 mg of the FHD 286 per day, wherein (i) the decitabine and (iii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, comprising 5.0 mg of FHD 286 or a pharmaceutically acceptable salt, per day, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

[0075] In some embodiments, (i) the decitabine is administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days. In some embodiments, (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day. In some embodiments, (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least fourteen days. In some embodiments, (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 5.0 mg per day. In some embodiments, (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 2 weeks.

[0076] In some embodiments, wherein the average daily dose during (a) the loading dose regimen is at least 3-fold higher than the average daily dose during (b) the maintenance dose regimen. In some embodiments, (a) the loading dose regimen comprises administering to the subject between about 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs. In some embodiments, (b) the maintenance dose regimen comprises administering to the subject between about 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, once daily. In some PATENT

[0077] ATTORNEY DOCKET NO.: 51121-109WO2 embodiments, (a) the loading dose regimen comprises administering to the subject between about 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs, followed by (b) the maintenance dose regimen comprises administering to the subject between about 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, step (b) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

[0078] In some embodiments, the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 12 hours of each other. In some embodiments, the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 1 day of each other.

[0079] In some embodiments, wherein decitabine, or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments, (ii) the differentiation dose regimen of FHD 286 is administered orally. In some embodiments, (iii) the maintenance dose regimen of FHD 286 is administered orally. In some embodiments, (a) the loading dose regimen of the isavuconazole, is administered orally or intravenously. In some embodiments, (b) the maintenance dose regimen of the isavuconazole, is administered orally, or intravenously.

[0080] In some embodiments, the pharmaceutically acceptable salt of isavuconazole is isavuconazonium sulfate.

[0081] In some embodiments, the method comprises at least 21 days of treatment. In some embodiments, the method comprises at least 28 days.

[0082] In some embodiments, the method comprises administering 1 , 2, or 3 cycles of decitabine. In some embodiments, the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering 1 , 2, or 3 cycles of (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering 1 , 2, or 3 cycles of (x) the antifungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering 1 , 2, or 3 cycles of (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt and (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof. In some embodiments, (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other. In some embodiments, (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.

[0083] In some embodiments, (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the antifungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other. In some embodiments, (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation PATENT

[0084] ATTORNEY DOCKET NO.: 51121-109WO2 dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

[0085] In some embodiments, the method comprises, at the completion of combination therapy in the subject, continuing to administer to the (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject (i) the decitabine, or a pharmaceutically acceptable salt thereof and / or (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises, at the completion of combination therapy in the subject, continuing to administer to the (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject (i) the decitabine, or a pharmaceutically acceptable salt thereof and / or (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments, hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome. In some embodiments, the hematologic cancer is acute myeloid leukemia. In some embodiments, the hematologic cancer is myelodysplastic syndrome.

[0087] In some embodiments, the risk of developing a fungal infection is reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof. In some embodiments, the fungal infection is aspergillosis or candidiasis.

[0088] In some embodiments of any of the above methods, wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, 13- cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments of any of the above methods, wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome. In some embodiments of any of the above methods, wherein the hematologic cancer is acute myeloid leukemia. In some embodiments of any of the above methods, wherein the hematologic cancer is myelodysplastic syndrome. In some embodiments of any of the above methods, wherein the hematologic cancer has an inv(3) mutation, a -7 / del(7q) mutation, a SF3E31 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and / or a DNMT3A mutation.

[0089] In some embodiments of any of the above methods, wherein the method inhibits cancer cell invasion or migration in a subject having a high risk of cancer cell invasion or migration. In some embodiments, wherein the method suppresses metastatic progression of cancer. In some embodiments, wherein the method suppresses metastatic colonization of cancer. In some embodiments, wherein the method slows the spread of a migrating cancer in a subject having a high risk of the spread of the migrating cancer. In some embodiments, wherein the method reduced the rate of tumor seeding of a cancer in a subject having a high risk of tumor seeding of a cancer. In some embodiments, wherein the PATENT

[0090] ATTORNEY DOCKET NO.: 51121-109WO2 method reduces or treats metastatic nodule-forming of a cancer in a subject having a high risk of metastatic nodule-forming of a cancer. In some embodiments, wherein the method reduces metastatic risk of a cancer in a subject having a high metastatic risk. In some embodiments, wherein the method treats metastatic cancer in a subject having a high metastatic risk. In some embodiments, wherein the method reduces tumor heterogeneity.

[0091] In some embodiments of any of the above methods, the hematological cancer is characterized by differentiation arrest.

[0092] In some embodiments of any of the above methods, the subject has been treated or is being treated for a hematological cancer is characterized by differentiation arrest.

[0093] In some embodiments of any of the above methods, the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.

[0094] In some embodiments, the hematological cancer has or has been determined to have inv(3) mutation. In some embodiments, the hematological cancer has or has been determined to have -7 / del(7q) mutation. In some embodiments, the hematological cancer has or has been determined to have SF3B1 mutation. In some embodiments, the hematological cancer has or has been determined to have MLLr mutation. In some embodiments, the hematological cancer has or has been determined to have RUNX1 mutation. In some embodiments, the hematological cancer has or has been determined to have ASXL1 mutation. In some embodiments, the hematological cancer has or has been determined to have JAK2 mutation. In some embodiments, the hematological cancer has or has been determined to have NRAS mutation. In some embodiments, the hematological cancer has or has been determined to have KRAS mutation. In some embodiments, the hematological cancer has or has been determined to have TP53 mutation. In some embodiments, the hematological cancer has or has been determined to have TET2 mutation. In some embodiments, the hematological cancer has or has been determined to have DNMT3 mutation. In some embodiments, the invention provides a method of treating hematological cancer in a subject, wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.

[0095] In some embodiments, the anti-fungal agent is polyene, amphotericin B, nystatin, natamycin, flucytosine, imidazole, miconazole, clotrimazole, econazole, ketoconazole, triazole, itraconazole, fluconazole, griseofulvin, terconazole, butoconazole, ciclopirox, ciclopirox olamine, haloprogin, tolnaftate, naftifine, orterbinafine.

[0096] In some embodiments, the anti-fungal agent is a CYP3A4 inhibitor (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole).

[0097] In some embodiments, the anti-fungal agent is itraconazole, ketoconazole, posaconazole, or voriconazole.

[0098] In some embodiments, the anti-fungal agent is itraconazole.

[0099] In some embodiments, the anti-fungal agent is ketoconazole.

[0100] In some embodiments, the anti-fungal agent is posaconazole.

[0101] In some embodiments, the anti-fungal agent is voriconazole.

[0102] In some embodiments, the fungal infection is aspergillosis or candidiasis. PATENT

[0103] ATTORNEY DOCKET NO.: 51121-109WO2

[0104] In some embodiments, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the decitabine, or a pharmaceutically acceptable salt thereof, alone.

[0105] In some embodiments, the invention provides a method of treating hematological cancer in a subject, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments of any of the above methods, the invention provides a method of depleting or promoting differentiation of blast cells of the leukemia in a subject in need thereof, the method comprising administering to the subject (i) FHD 286, or a pharmaceutically acceptable salt thereof, and (ii) Decitabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective in treating hematological cancer.

[0107] In some embodiments, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments of any of the above methods, wherein (iv) the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin. In some embodiments of any of the above methods, wherein the anti-fungal agent is a CYP3A4 inhibitor. In some embodiments of any of the above methods, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, or voriconazole. In some embodiments of any of the above methods, wherein the fungal infection is aspergillosis or candidiasis. In some embodiments of any of the above methods, wherein (x) the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin. In some embodiments of any of the above methods, wherein the anti-fungal agent is a CYP3A4 inhibitor. In some embodiments of any of the above methods, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, or voriconazole. In some embodiments of any of the above methods, wherein the fungal infection is aspergillosis or candidiasis.

[0109] In another aspect, the present invention features a method for treating hematologic cancer in a subject in need thereof, the method comprising administering to the subject (x) an anti-fungal agent, or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection, and (y): (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation PATENT

[0110] ATTORNEY DOCKET NO.: 51121-109WO2 dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen .

[0111] In some embodiments of any of the above methods, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments of any of the above methods, wherein (iv) the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin. In some embodiments of any of the above methods, wherein (iv) the anti-fungal agent is a CYP3A4 inhibitor. In some embodiments of any of the above methods, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, and voriconazole. In some embodiments of any of the above methods, wherein the fungal infection is aspergillosis or candidiasis.

[0113] In some embodiments of any of the above methods, wherein (x) the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin. In some embodiments of any of the above methods, wherein (iv) the anti-fungal agent is a CYP3A4 inhibitor. In some embodiments of any of the above methods, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, and voriconazole. In some embodiments of any of the above methods, wherein the fungal infection is aspergillosis or candidiasis.

[0114] In some embodiments, the method includes at least 21 days, 28 days, 2 months, 3 months, 4 months, or 6 months of treatment.

[0115] Definitions

[0116] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.

[0117] As used herein, the term “hematologic cancer,” refers to cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system, e.g., leukemias, lymphomas, and PATENT

[0118] ATTORNEY DOCKET NO.: 51121-109WO2 myelomas. Leukemias are cancers found in blood and bone marrow which are caused by rapid production of abnormal white blood cells. Lymphomas are cancers which affect the lymphatic system. Myelomas are cancers of the plasma cells. In most hematologic cancers, normal blood cell development is interrupted by uncontrolled growth of an abnormal type of blood cell. The abnormal blood cells prevent the blood from performing many of its functions. Hematologic cancers account for about 10% of all new cancer diagnoses. The 5-year relative survival rates for hematologic cancers range from about 50% to about 90%.

[0119] As used herein, the term “FHD 286” refers to N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide. As used herein, FHD 286 has the structure:

[0120] As used herein, the term “decitabine’ refers to 5-aza-2'-deoxycytidine. As used herein, decitabine has the structure:

[0121] As used herein, the term “anti-fungal agent” refers to an agent that when administered to a host selectively suppresses the growth of, or kills, fungi in the host, including but not limited to polyene antifungals (e.g., natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, hamycin), imidazole antifungals (e.g., miconazole (MICATIN®, DAKTARIN®), ketoconazole (NIZORAL®, FUNGORAL®, SEBIZOLE®), clotrimazole (LOTRIMIN®, LOTRIMIN® AF, CANESTEN®), econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole (ERTACZO®), sulconazole, tioconazole), triazole antifungals (e.g., albaconazole fluconazole, itraconazole (SPORANOX or TOLSURA®), isavuconazole (CRESEMBA®), ravuconazole, posaconazole, voriconazole, terconazole), thiazole antifungals (e.g., abafungin), allylamines (e.g., terbinafine (LAMISIL®), naftifine (NAFTIN®), butenafine (LOTRIMIN® Ultra)), echinocandins (e.g., anidulafungin, caspofungin, micafungin), and others (e.g., polygodial, benzoic acid, ciclopirox, tolnaftate (TINACTIN®, DESENEX®, AFTATE®), undecylenic acid, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, sodium bicarbonate, allicin).

[0122] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

[0123] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, PATENT

[0124] ATTORNEY DOCKET NO.: 51121-109WO2 subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.

[0125] As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.

[0126] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0127] A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.

[0128] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound described herein. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, PATENT

[0129] ATTORNEY DOCKET NO.: 51121-109WO2

[0130] (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting a free base group with a suitable organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be, e.g., acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable nontoxic acids and bases including inorganic and organic acids and bases.

[0131] As used herein, the term “progression-free survival” as used herein, refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse. The combination therapies of the invention can increase the likelihood of progression-free survival in a subject.

[0132] As used herein, the term “proliferation” as used in this application involves reproduction or multiplication of similar forms (cells) due to constituting (cellular) elements. The combination therapies of the invention can decrease proliferation of cancer cells.

[0133] As used herein, the term “subject” refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[0134] As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. In the context of treating cancer, treatment may include slowing the spread of metastasis and / or extending progression-free survival in a population of treated subjects as compared to a population of untreated subjects.

[0135] As used herein, the terms “reduce the risk of a fungal infection” refers to reducing the likelihood that a patient acquires a fungal infection (e.g. aspergillosis or candidiasis) while undergoing a treatment of the invention. A reduced risk of a fungal infection is assessed for a given patient population (e.g. patients who are undergoing treatment of hematological cancer according to the methods of the invention), where the likelihood of a fungal infection for a subject receiving FHD-286, decitabine, and an anti-fungal agent is PATENT

[0136] ATTORNEY DOCKET NO.: 51121-109WO2 reduced relative to patients receiving an identical treatment regimen, but without any concurrent antifungal therapy. The likelihood of fungal infection can be reduced, e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, using the methods described herein.

[0137] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0138] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0139] DETAILED DESCRIPTION OF THE INVENTION

[0140] The present disclosure features combination therapies including FHD 286, decitabine, and optionally, an anti-fungal agent for the treatment of AML and related hematological cancers. The combination therapies of the invention can reduce side effects, improve outcomes, and / or reduce the dosing burden on the patient. For example, using the methods described herein the risk of developing differentiation syndrome can be reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the decitabine, or a pharmaceutically acceptable salt thereof, alone. In some embodiments, the methods of the present disclosure result in one or more (e.g., two or more, three or more, four or more) of: (a) decrease blast count, (b) normal neutrophil counts, (c) normal platelet counts, (d) a bone marrow biopsy which reveals no clusters or collections of blast cells, (e) decreased tumor recurrence (f) increased survival of subject, (g) increased progression free survival of subject. Additionally, using the methods described herein, the risk of developing a fungal infection is reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the decitabine or a pharmaceutically acceptable salt thereof, alone.

[0141] Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention. PATENT

[0142] ATTORNEY DOCKET NO.: 51121-109WO2

[0143] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

[0144] Exemplary hematological cancers that may be treated by the invention include, but are not limited to multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or nonHodgkin’s lymphoma.

[0145] The hematologic cancer can be characterized as having an inv(3) mutation, a -7 / del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and / or a DNMT3A mutation.

[0146] N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)- 1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (FHD 286)

[0147] The methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen. Methods for synthesizing FHD 286 are described in International Application No. PCT / US2021 / 015876, the content of which is incorporated herein by reference in its entirety. Methods of treatment of FHD 286 are described in International Application No. PCT / US2021 / 015876, the content of which is incorporated herein by reference in its entirety. Methods of treating cancer by FHD 286 are described in International Application No. PCT / US23 / 17829, the content of which is incorporated herein by reference in its entirety.

[0148] In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 7.5 mg and about 22.5 mg per day. In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 7.5 mg and about 10 mg per day. In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 10.0 mg and about 12.5 mg per day. In some PATENT

[0149] ATTORNEY DOCKET NO.: 51121-109WO2 embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 12.5 mg and about 15.0. In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 15.0 mg and about 17.5 mg per day. In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 17.5 mg and about 20 mg per day. In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 20 mg and about 22.5 mg per day. In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose between about 20 mg and about 22.5 mg per day. In some embodiments, wherein (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day. In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose of about 7.5 mg per day. In some embodiments, (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least fourteen days.

[0150] In some embodiments, (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, is administered in total dose between about 1 .5 mg and about 2.5 mg per day. In some embodiments, (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, is administered in total between about 2.5 mg and about 5 mg per day. In some embodiments, (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, is administered in total dose between about 5 mg and about 7.0 mg per day. In some embodiments, wherein (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 1 .5 mg per day, about 2.0 mg per day, subject about 2.5 mg per day, about 3.0 mg per day, subject about 3.5 mg per day, about 4.0 mg per day, subject about 4.5 mg per day, about 5.0 mg per day, subject about 5.5 mg per day, about 6.0 mg per day, about 6.5 mg per day, or about 7.0 mg per day. In some embodiments, (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose of about 5.0 mg per day. In some embodiments, (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least fourteen days.

[0151] In some embodiments, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose of about 7.5 mg per day for a period of at least fourteen days, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof is administered in total dose of about 5.0 mg per day for a period of at least fourteen days.

[0152] Additional details are provided in the Examples.

[0153] Decitabine

[0154] The methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, each in an amount that together is PATENT

[0155] ATTORNEY DOCKET NO.: 51121-109WO2 effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen. Methods of treatment of decitabine are described in US Application No. US20050222076A1 , the content of which is incorporated herein by reference in its entirety. Decitabine is approved for use by the FDA under the name DACOGEN®.

[0156] In some embodiments, decitabine or a pharmaceutically acceptable salt thereof is administered at a dose of 15 mg / m2by continuous intravenous transfusion over 3 hours repeated every 8 hours for 3 days (i.e., low dose decitabine) in a cycle optionally repeated every 6 weeks. In some embodiments, decitabine or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days (i.e., high dose decitabine) in a cycle optionally repeated every 4 weeks. The combination therapy can include, one, two, three, or more cycles of decitabine administered in combination with FHD 286 treatment.

[0157] Anti-fungal Agent

[0158] The methods of the invention include treating hematologic cancer in a subject by administering to the subject an anti-fungal agent or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection, and (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen. In particular embodiments, the method can further include administering an anti-fungal agent to reduce the risk of fungal infection in the subject. In particular embodiments, the anti-fungal agent is a CYP3A4 inhibitor. For example, the anti-fungal agent can be posaconazole, which is approved for use by the FDA under the name NOXAFIL®. For example, the anti-fungal agent can be itraconazole, which is approved for use by the FDA under the name SPORANOX® or TOLSURA®. For example, the anti-fungal agent can be fluconazole, which is approved for use by the FDA under the name DIFLUCAN® or FUMYCIN®. For example, the anti-fungal agent can be isavuconazole, which is approved for use by the FDA under the name CRESEMBA®. For example, the anti-fungal agent can be amphotericin B, which is approved for use by the FDA under the name VFEND®. For example, the anti-fungal agent can be voriconazole, which is approved for use by the FDA under the name AMBISOME® or FUNGIZONE®. For example, the antifungal agent can be clotrimazole, which is approved for use by the FDA under the name LOTRIMIN®, LOTRIMIN® AF, or CANESTEN®. For example, the anti-fungal agent can be miconazole, which is approved for use by the FDA under the name MICATIN®, or DAKTARIN®. For example, the anti-fungal PATENT

[0159] ATTORNEY DOCKET NO.: 51121-109WO2 agent can be nystatin, which is approved for use by the FDA under the name BIO-STATIN®. For example, the anti-fungal agent can be anidulafungin (an echinocandin), which is approved for use by the FDA under the name ERAXIS® or ECALTA®. For example, the anti-fungal agent can be caspofungin (an echinocandin), which is approved for use by the FDA under the name CANCIDAS®. For example, the anti-fungal agent can be micafungin (an echinocandin), which is approved for use by the FDA under the name MYCAMINE®. For example, the anti-fungal agent can be ketoconazole, which is approved for use by the FDA under the name NIZORAL®, FUNGORAL®, SEBIZOLE®. For example, the anti-fungal agent can be sertaconazole, which is approved for use by the FDA under the name ERTACZO®. For example, the anti-fungal agent can be tolnaftate, which is approved for use by the FDA under the name TINACTIN®, DESENEX®, or AFT ATE®. Other anti-fungal agents can also be used.

[0160] In some embodiments, wherein the anti-fungal agent is administered as a (a) a loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (a), administering to the subject (b) a maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (a) the loading dose regimen and (b) the maintenance dose regimen together are effective to reduce the risk of a fungal infection, and wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen.

[0161] In some embodiments, (a) the loading dose regimen comprises (1) between about 200 mg and about 400 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (2) between about 200 mg and about 225 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (3) between about 225 mg and about 250 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (4) between about 250 mg and about 275 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (5) between about 275 mg and about 300 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, (6) between about 300 mg and about 325 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (7) between about 325 mg and about 350 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (8) between about 350 mg and about 375 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (9) between about 375 mg and about 400 mg per day at least three times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, (b) the maintenance dose regimen comprises (1) between about 200 mg and about 400 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (2) between about 200 mg and about 225 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (3) between about 225 mg and about 250 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (4) between about 250 mg and about 275 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (5) between about 275 mg and about 300 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (6) between about 300 mg and about 325 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically PATENT

[0163] ATTORNEY DOCKET NO.: 51121-109WO2 acceptable salt thereof, or (7) between about 325 mg and about 350 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (8) between about 350 mg and about 375 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or (9) between about 375 mg and about 400 mg per day at least once daily of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments of any of the above methods, wherein the anti-fungal agent is isavuconazole, which is approved for use by the FDA under the name CRESEMBA®. In some embodiments, (a) the loading dose regimen comprises (1) between about 200 mg and about 400 mg per day at least three times a day of the isavuconazole, and (b) the maintenance dose regimen comprises (1) between about 200 mg and about 400 mg per day at least once daily of the isavuconazole. In some embodiments, (a) the loading dose regimen comprises about 200 mg per day at least three times a day of the isavuconazole, and (b) the maintenance dose regimen comprises 200 mg per day at least once daily of the isavuconazole.

[0165] In some embodiments of any of the above methods, wherein the anti-fungal agent is isavuconazonium sulfate. In some embodiments, (a) the loading dose regimen comprises 372 mg per day at least three times a day of the isavuconazole, and (b) the maintenance dose regimen comprises 372 mg per day at least once daily of the isavuconazole.

[0166] In some embodiments of any of the above methods, wherein the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments of any of the above methods, wherein the isavuconazole, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments of any of the above methods, wherein the isavuconazole, or a pharmaceutically acceptable salt thereof, is administered intravenously.

[0167] In some embodiments, the anti-fungal agent or a pharmaceutically acceptable salt thereof is administered as a low dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 2.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-fungal agent or a pharmaceutically acceptable salt thereof is administered as a high dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 7.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, step (c) of the low dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. In some embodiments, step (d) of the low dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. In some embodiments, step (e) of the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. In some embodiments, step (f) of the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. The combination therapy can include, one, two, three, or more cycles of the PATENT

[0168] ATTORNEY DOCKET NO.: 51121-109WO2 low dose regimen of the anti-fungal agent administered in combination with FHD 286 treatment and / or decitabine treatment. The combination therapy can include, one, two, three, or more cycles of the high dose regimen of the anti-fungal agent administered in combination with FHD 286 treatment and / or decitabine treatment.

[0169] Pharmaceutical Compositions

[0170] The compounds of the present disclosure may be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include an active agent as described herein and a physiologically acceptable excipient (e.g., a pharmaceutically acceptable excipient). Formulation principles for the compounds disclosed herein may be those described, e.g., in WO 2020 / 160180, the disclosure of which is incorporated by reference herein in its entirety.

[0171] The compounds of the disclosure may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, ortransdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Preferably, the compound is administered orally.

[0172] Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary).

[0173] In one embodiment, the FHD 286 may be formulated into a unit dosage form for oral administration (e.g., a capsule) as described in Table 1 .

[0174] Examples

[0175] The cell culture method, flow cytometry method and flow cytometry analysis methods are relevant to the examples below.

[0176] Example 1. A study of a differentiation dose regimen and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and high dose decitabine for the treatment of acute myeloid leukemia (AML).

[0177] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other.

[0178] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. PATENT

[0179] ATTORNEY DOCKET NO.: 51121-109WO2

[0180] The cycle is repeated multiple times, as needed. For some responsive patients, the (ii) differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with decitabine for a period of at least one month, two months, three months, or four months. Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 20 mg / m2administered to subjects over 1 hour repeated daily for 5 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 4 weeks, as needed. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0181] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts overtime, relative to either treatment with FHD 286 alone or decitabine alone.

[0182] Example 2. A study of a differentiation dose regimen and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof and low dose decitabine for the treatment of acute myeloid leukemia (AML) with pre-treatment of FHD 286.

[0183] Subjects with acute myeloid leukemia (AML) are treated with a differentiation and maintenance dose regimen of FHD 286 administered orally in combination with low dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy by first receiving a treatment with FHD 286, followed by treatment with both drugs.

[0184] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, the (ii) differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with decitabine for a period of at least one month, two months, three months, or four months.

[0185] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 15 mg / m2administered to subjects over 3 hours repeated every 8 hours for 3 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 6 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0186] Subjects receiving the combination of differentiation and maintenance dose regimen of FHD 286 and low dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome PATENT

[0187] ATTORNEY DOCKET NO.: 51121-109WO2 and / or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with differentiation and maintenance dose regimen of FHD 286alone or decitabine alone.

[0188] Example 3. A study of a differentiation dose regimen and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and high dose decitabine for the treatment of acute myeloid leukemia (AML) with pre-treatment of FHD 286.

[0189] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy by first receiving a treatment with FHD 286, followed by treatment with both drugs.

[0190] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine for a period of at least one month, two months, three months, or four months.

[0191] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 20 mg / m2administered to subjects over 1 hour repeated daily for 5 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 4 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with a differentiation dose regimen and maintenance dose regimen of FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0192] Subjects receiving the combination of a differentiation dose regimen and maintenance dose regimen of FHD 286and low dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts overtime, relative to either treatment with a differentiation dose regimen and maintenance dose regimen of FHD 286 alone or decitabine alone.

[0193] Example 4. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, high dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of an anti-fungal agent to reduce the risk of a fungal infection.

[0194] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other. PATENT

[0195] ATTORNEY DOCKET NO.: 51121-109WO2

[0196] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or the anti-fungal agent for a period of at least one month, two months, three months, or four months.

[0197] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 20 mg / m2administered to subjects over 1 hour repeated daily for 5 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 4 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0198] The anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of between about 200 mg to 400 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg and 400 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0199] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts overtime, relative to either treatment with FHD 286 alone or decitabine alone.

[0200] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of an anti-fungal agent can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0201] Example 5. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, low dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of an anti-fungal agent to reduce the risk of a fungal infection.

[0202] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other.

[0203] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance PATENT

[0204] ATTORNEY DOCKET NO.: 51121-109WO2 dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or the anti-fungal agent for a period of at least one month, two months, three months, or four months.

[0205] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 15 mg / m2administered to subjects over 3 hours repeated every 8 hours for 3 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 6 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0206] The anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of between about 200 mg to 400 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg and 400 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0207] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with FHD 286 alone or decitabine alone.

[0208] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of an anti-fungal agent can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0209] Example 6. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, high dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of an anti-fungal agent to reduce the risk of a fungal infection with pre-treatment of FHD 286.

[0210] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy by first receiving a treatment with FHD 286, followed by treatment with both drugs.

[0211] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients PATENT

[0212] ATTORNEY DOCKET NO.: 51121-109WO2 continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or the anti-fungal agent for a period of at least one month, two months, three months, or four months.

[0213] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 20 mg / m2administered to subjects over 1 hour repeated daily for 5 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 4 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0214] The anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of between about 200 mg to 400 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg and 400 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0215] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with FHD 286 alone or decitabine alone.

[0216] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of an anti-fungal agent can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0217] Example 7. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, low dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of an anti-fungal agent to reduce the risk of a fungal infection with pre-treatment of FHD 286.

[0218] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy by first receiving a treatment with FHD 286, followed by treatment with both drugs.

[0219] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or the anti-fungal agent for a period of at least one month, two months, three months, or four months.

[0220] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 15 mg / m2administered to subjects over 3 hours repeated every 8 hours for 3 days, PATENT

[0221] ATTORNEY DOCKET NO.: 51121-109WO2 followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 6 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0222] The anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of between about 200 mg to 400 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg and 400 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0223] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts overtime, relative to either treatment with FHD 286 alone or decitabine alone.

[0224] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of an anti-fungal agent can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0225] Example 8. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, high dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, to reduce the risk of a fungal infection.

[0226] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other.

[0227] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or isavuconazole, or a pharmaceutically acceptable salt thereof, for a period of at least one month, two months, three months, or four months.

[0228] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 20 mg / m2administered to subjects over 1 hour repeated daily for 5 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 4 PATENT

[0229] ATTORNEY DOCKET NO.: 51121-109WO2 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0230] The isavuconazole, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of about 200 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0231] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with FHD 286 alone or decitabine alone.

[0232] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0233] Example 9. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, low dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, to reduce the risk of a fungal infection.

[0234] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other.

[0235] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or isavuconazole, or a pharmaceutically acceptable salt thereof, for a period of at least one month, two months, three months, or four months.

[0236] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 15 mg / m2administered to subjects over 3 hours repeated every 8 hours for 3 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 6 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, PATENT

[0237] ATTORNEY DOCKET NO.: 51121-109WO2 or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0238] The isavuconazole, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of about 200 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0239] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with FHD 286 alone or decitabine alone.

[0240] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0241] Example 10. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, high dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, to reduce the risk of a fungal infection with pretreatment of FHD 286.

[0242] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy by first receiving a treatment with FHD 286, followed by treatment with both drugs.

[0243] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or isavuconazole, or a pharmaceutically acceptable salt thereof, for a period of at least one month, two months, three months, or four months.

[0244] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 20 mg / m2administered to subjects over 1 hour repeated daily for 5 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 4 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one PATENT

[0245] ATTORNEY DOCKET NO.: 51121-109WO2 full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0246] The isavuconazole, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of about 200 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0247] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with FHD 286 alone or decitabine alone.

[0248] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0249] Example 11. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, low dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, to reduce the risk of a fungal infection with pretreatment of FHD 286.

[0250] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy by first receiving a treatment with FHD 286, followed by treatment with both drugs.

[0251] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of between about 7.5 mg to 22.5 mg per day for about six to fifteen days, followed by the maintenance dose which has a total dose of between about 1 .5 mg and 7.0 mg per day for about six to fifteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or isavuconazole, or a pharmaceutically acceptable salt thereof, for a period of at least one month, two months, three months, or four months.

[0252] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 15 mg / m2administered to subjects over 3 hours repeated every 8 hours for 3 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 6 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is PATENT

[0253] ATTORNEY DOCKET NO.: 51121-109WO2 discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0254] The isavuconazole, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of about 200 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0255] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with FHD 286 alone or decitabine alone.

[0256] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0257] Example 12. A study of a differentiation and maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, high dose decitabine for the treatment of acute myeloid leukemia (AML), and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, to reduce the risk of a fungal infection.

[0258] Subjects with acute myeloid leukemia (AML) are treated with a differentiation dose regimen and maintenance dose regimen of FHD 286 administered orally in combination with high dose decitabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other.

[0259] FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally in a differentiation dose regimen and maintenance dose regimen in which the differentiation dose regimen has a total dose of about 7.5 mg per day for about fourteen days, followed by the maintenance dose which has a total dose of about 5.0 mg per day for about fourteen days. The cycle is repeated multiple times, as needed. For some responsive patients, (ii) the differentiation dose regimen is discontinued after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with (iii) the maintenance dose of FHD 286 alone or with (i) decitabine and / or isavuconazole, or a pharmaceutically acceptable salt thereof, for a period of at least one month, two months, three months, or four months.

[0260] Decitabine is administered by continuous intravenous infusion in a cyclical on / off dosing regimen with a dose of 20 mg / m2administered to subjects over 1 hour repeated daily for 5 days, followed by a period without any decitabine administration. The decitabine treatment is optionally repeated every 4 weeks, as needed. Decitabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286. For some responsive patients decitabine treatment is discontinued PATENT

[0261] ATTORNEY DOCKET NO.: 51121-109WO2 after three cycles, two cycles, or one cycle, after which the patients continue to receive treatment with FHD 286 alone for a period of at least one month, two months, three months, or four months.

[0262] The isavuconazole, or a pharmaceutically acceptable salt thereof, is administered in a loading and maintenance dose regimen in which the loading dose regimen has a total dose of about 200 mg per day at least three times per day for 48 hours, followed by the maintenance dose which has a total dose of between about 200 mg per day once daily for about six to fifteen days. The cycle is repeated multiple times, as needed.

[0263] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286 and high dose decitabine can benefit from a reduction in the risk of developing differentiation syndrome and / or benefit from a reduction in the number of peripheral blasts overtime, relative to either treatment with FHD 286 alone or decitabine alone.

[0264] Subjects receiving the combination of the differentiation and maintenance dose regimen of FHD 286. high dose decitabine and a loading and maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, can benefit from a reduction in the risk of developing a fungal infection, relative to either treatment with FHD 286 alone or decitabine alone or the combination of FHD 286 and Decitabine.

[0265] Other Embodiments

[0266] While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0267] Other embodiments are in the claims.

Claims

PATENTATTORNEY DOCKET NO.: 51121-109WO2What is claimed is:CLAIMS1 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

2. The method of claim 1 , the method further comprising administering to the subject (iv) an antifungal agent or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection.

3. The method of claim 2, wherein (iv) the anti-fungal agent is administered as a (a) a loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (a), administering to the subject (b) a maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (a) the loading dose regimen and (b) the maintenance dose regimen together are effective to reduce the risk of a fungal infection, and wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen.

4. The method of any one of claims 1-3, wherein (i) the decitabine is administered at a dose of 15 mg / m2by continuous intravenous transfusion over 3 hours repeated every 8 hours for 3 days.

5. The method of any one of claims 1-3, wherein (i) the decitabine is administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days.

6. The method of any one of claims 1 to 5, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, are administered within 24 hours of each other.

7. The method of any one of claims 1 -6, wherein (ii) the differentiation dose regimen is sufficient to produce a Caverage plasma concentration level of at least 250 ng / mL in the subject, and the maintenance dose regimen is sufficient to produce a Caverage plasma concentration level of between about 80 ng / mL and about 225 ng / mL in the subject.PATENTATTORNEY DOCKET NO.: 51121-109WO28. The method of any one of claims 1-7, wherein (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day.

9. The method of any one of claims 1-7, wherein (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day.

10. The method of any one of claims 1-9, wherein (ii) the differentiation dose regimen comprising administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to twenty-eight days.11 . The method of claim 10, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

12. The method of claim 11 , wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to ten days.

13. The method of claim 12, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to five days.

14. The method of claim 13, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of one day.

15. The method of any one of claims 1-14, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more every ten days to fourteen days.

16. The method of claim 15, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more weekly.

17. The method of claim 16, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject at least once daily.

18. The method of any one of claims 1-17, wherein (ii) the differentiation dose regimen comprises administering FHD 286, or a pharmaceutically acceptable salt thereof, at an average daily dose of between about 7.5 mg to 22.5 mg.PATENTATTORNEY DOCKET NO.: 51121-109WO219. The method of any one of claims 1-18, wherein (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 1 .5 mg per day, about 2.0 mg per day, subject about 2.5 mg per day, about 3.0 mg per day, about 3.5 mg per day, about 4.0 mg per day, about 4.5 mg per day, about 5.0 mg per day, about 5.5 mg per day, about 6.0 mg per day, about 6.5 mg per day, or about 7.0 mg per day.

20. The method of any one of claims 1-19, wherein (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 5.0 mg per day.21 . The method of any one of claims 1 -7, wherein (ii) the differentiation dose regimen comprises administering daily to the subject between about 7.5 mg to 22.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen comprises administering daily to the subject from 1 .5 mg to 7.0 mg of FHD 286, or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 1 -21 , wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more every ten to fourteen days.

23. The method of claim 22, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject once or more weekly.

24. The method of claim 23, wherein the maintenance dose of FHD 286 is administered to the subject at least once daily.

25. The method of any one of claims 1-24, wherein (iii) the maintenance dose regimen comprises administering FHD 286, or a pharmaceutically acceptable salt thereof, at an average daily dose of from 1 .0 mg to 7.0 mg.

26. The method of any one of claims 1-25, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 2 weeks.

27. The method of claim 26, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one month.

28. The method of claim 27, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 3 months.

29. The method of claim 28, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least six months.PATENTATTORNEY DOCKET NO.: 51121-109WO230. The method of claim 29, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 12 months.31 . The method of any one of claims 1-30, wherein the ratio of the average daily dose of FHD 286, or a pharmaceutically acceptable salt thereof, administered during (ii) the differentiation dose regimen to the average daily dose of FHD 286, or a pharmaceutically acceptable salt thereof, administered during (iii) the maintenance dose regimen is from 10:1 to 1.25:1.

32. The method of any one of claims 1 -31 , wherein the final dose of (ii) the differentiation dose regimen and the first dose of (iii) the maintenance dose regimen are administered within 1 day of each other.

33. The method of any one of claims 1 -31 , wherein the final dose of (ii) the differentiation dose regimen and the first dose of the (iii) maintenance dose regimen are administered within 28 days of each other.

34. The method of any one of claims 3-33, wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen.

35. The method of any one of claims 3-34, wherein (a) the loading dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least twice daily.

36. The method of any one of claims 3-35, wherein (b) the maintenance dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least once daily.

37. The method of any one of claims 3-36, wherein (a) the loading dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least twice daily, followed by (b) the maintenance dose regimen comprises administering to the subject about 300 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least once daily.

38. The method of any one of claims 3-33, wherein the average daily dose during (a) the loading dose regimen is at least 3-fold higher than the average daily dose during (b) the maintenance dose regimen.

39. The method of any one of claims 3-33 and 38, wherein (a) the loading dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs.PATENTATTORNEY DOCKET NO.: 51121-109WO240. The method of any one of claims 3-33 and 38-39, wherein (b) the maintenance dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, once daily.41 . The method of any one of claims 3-33 and 38-40, wherein (a) the loading dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs, followed by (b) the maintenance dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, once daily.

42. The method of any one of claims 3-41 , wherein (a) the loading dose regimen comprises administering the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at an average daily dose of between about 600 mg to 1200 mg.

43. The method of any one of claims 3-42, wherein (b) the maintenance dose regimen comprises administering FHD 286, or a pharmaceutically acceptable salt thereof, at an average daily dose of between about 200 mg to 400 mg.

44. The method of any one of claims 3-43, wherein (a) the loading dose regimen comprises administering the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at an average daily dose of about 600 mg.

45. The method of claim 3-43, wherein step (a) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 48 hours.

46. The method of claim 3-45, wherein step (b) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

47. The method of any one of claims 3-46, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 12 hours of each other.

48. The method of any one of claims 3-46, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 1 day of each other.

49. The method of any one of claims 3-33 and 38-46, wherein the final dose of (a) the loading dose regimen and the first dose of the (b) maintenance dose regimen are administered within 28 days of each other.PATENTATTORNEY DOCKET NO.: 51121-109WO250. The method of claim 2, wherein (iv) the anti-fungal agent is administered as a (c) a low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (c), administering to the subject (d) a high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (c) the low dose regimen and (d) the high dose regimen together are effective to reduce the risk of a fungal infection.51 . The method of claim 50, wherein (c) the low dose regimen comprises administering to the subject between about 2.5 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days followed by (d) the high dose regimen comprises administering to the subject about 5.0 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days.

52. The method of claim 51 , wherein (c) the low dose regimen comprises administering to the subject between about 5.0 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days followed by (d) the high dose regimen comprises administering to the subject about 7.5 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at least four times a day for ten to 20 days.

53. The method of claim 50-52, wherein step (c) comprises administering to the subject the antifungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

54. The method of claim 50-53, wherein step (c) comprises administering to the subject the antifungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 48 hours.

55. The method of claim 40-54, wherein step (d) comprises administering to the subject the antifungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

56. The method of any one of claims 50-55, wherein the final dose of (c) the low dose regimen and the first dose of (d) the high dose regimen are administered within 12 hours of each other.

57. The method of any one of claims 50-56, wherein the final dose of (c) the low dose regimen and the first dose of (d) the high dose regimen are administered within 1 day of each other.

58. The method of any one of claims 50-57, wherein the final dose of (c) the low dose regimen and the first dose of (d) the high dose regimen are administered within 28 days of each other.

59. The method of any one of claims 1-58, wherein decitabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.PATENTATTORNEY DOCKET NO.: 51121-109WO260. The method of any one of claims 1-59, wherein (ii) the differentiation dose regimen of FHD 286 is administered orally.

61. The method of any one of claims 1-60, wherein (iii) the maintenance dose regimen of FHD 286 is administered orally.

62. The method of any one of claims 2-61 , wherein (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered orally.

63. The method of any one of claims 2-61 , wherein (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered intravenously.

64. The method of any one of claims 3-49 and 59-61 , wherein (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally.

65. The method of any one of claims 3-49 and 59-61 , wherein (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered intravenously.

66. The method of any one of claims 3-49,59-61 and 63-65, wherein (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally.

67. The method of any one of claims 3-49, 59-61 and 63-65, wherein (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, is intravenously.

68. The method of any one of claims 50-61 , wherein (c) the low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally or intravenously.

69. The method of any one of claims 50-61 , wherein (d) the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally.

70. The method of any one of claims 50-61 and 68-69, wherein (d) the high dose regimen of the antifungal agent or a pharmaceutically acceptable salt thereof, is intravenously.71 . The method of any one of claims 1-70, wherein the method comprises at least 21 days of treatment.

72. The method of any one of claims 1-71 , wherein the method comprises at least 28 days of treatment.

73. The method of any one of claims 1-72, wherein the method comprises administering 1 , 2, or 3 cycles of decitabine.PATENTATTORNEY DOCKET NO.: 51121-109WO274. The method of any one of claims 1-73, wherein the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

75. The method of any one of claims 1-74, wherein the method comprises administering 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

76. The method of any one of claims 1-74, wherein the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

77. The method of any one of claims 1-74, wherein the method comprises administering 1 cycle of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

78. The method of any one of claims 2-77, wherein the method comprises administering 1 , 2, or 3 cycles of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

79. The method of any one of claims 3-49 and 59-77, wherein the method comprises administering 1 , 2, or 3 cycles of (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt and (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof.

80. The method of any one of claims 50-61 and 68-76, wherein the method comprises administering 1 , 2, or 3 cycles of (c) the low dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt and (d) the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof.81 . The method of any one of claims 2-80, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.

82. The method of any one of claims 2-80, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

83. The method of any one of claims 2-80, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iv) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.PATENTATTORNEY DOCKET NO.: 51121-109WO284. The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.

85. The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

86. The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

87. The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.

88. The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 18 hours of each other.

89. The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

90. The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 2 days of each other.91 . The method of any one of claims 3-49, 59-67, and 71-79, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

92. The method of any one of claims 3-49, 59-67, and 71-79, wherein (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.PATENTATTORNEY DOCKET NO.: 51121-109WO293. The method of any one of claims 3-49, 59-67, and 71-79, wherein (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

94. The method of any one of claims 3-49, 59-67, and 71-79, wherein (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (a) the loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

95. The method of any one of claims 3-49, 59-67, 71-77, and 84-94, wherein (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.

96. The method of any one of claims 3-49, 59-67, 71-77, and 84-94, wherein (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

97. The method of any one of claims 3-49, 59-67, 71-77, and 84-94, wherein (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.

98. The method of any one of claims 1-97, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof.

99. The method of any one of claims 1-97, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof.

100. The method of any one of claims 1-97, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof.PATENTATTORNEY DOCKET NO.: 51121-109WO2101. The method of any one of claims 1-97, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, without further administering to the subject decitabine, or a pharmaceutically acceptable salt thereof.

102. The method of any one of claims 2-97, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (iv) the antifungal agent, or a pharmaceutically acceptable salt thereof.

103. The method of any one of claims 2-97, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

104. The method of any one of claims 2-97, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof and / or a dose of (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

105. The method of any one of claims 2-97, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject (i) the decitabine, or a pharmaceutically acceptable salt thereof and / or (iv) the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

106. The method of any one of claims 1-105, wherein (ii) the differentiation dose regimen is sufficient to induce cell arrest and / or apoptosis in leukemic stem cells in a subject and (iii) the maintenance dose regimen is insufficient to induce cell arrest and / or apoptosis in leukemic stem cells in a subject, but sufficient to reduce the number of blast cells.

107. The method of any one of claims 1-106, wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.PATENTATTORNEY DOCKET NO.: 51121-109WO2108. The method of any one of claims 1-107, wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.

109. The method of any one of claims 1-106, wherein the hematologic cancer is acute myeloid leukemia.

110. The method of any one of claims 1-106, wherein the hematologic cancer is myelodysplastic syndrome.

111. The method of any one of claims 1-110, wherein the hematologic cancer has an inv(3) mutation, a -7 / del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and / or a DNMT3A mutation.

112. The method of any one of claims 1-111 , wherein the method inhibits cancer cell invasion or migration in a subject having a high risk of cancer cell invasion or migration.

113. The method of any one of claims 1-112, wherein the method suppresses metastatic progression of cancer.

114. The method of any one of claims 1-113, wherein the method suppresses metastatic colonization of cancer.

115. The method of any one of claims 1-114, wherein the method slows the spread of a migrating cancer in a subject having a high risk of the spread of the migrating cancer.

116. The method of any one of claims 1-115, wherein the method reduced the rate of tumor seeding of a cancer in a subject having a high risk of tumor seeding of a cancer.

117. The method of any one of claims 1-116, wherein the method reduces or treats metastatic noduleforming of a cancer in a subject having a high risk of metastatic nodule-forming of a cancer.

118. The method of any one of claims 1-117, wherein the method reduces metastatic risk of a cancer in a subject having a high metastatic risk.

119. The method of any one of claims 1-118, wherein the method treats metastatic cancer in a subject having a high metastatic risk.

120. The method of any one of claims 1-119, wherein the method reduces tumor heterogeneity.PATENTATTORNEY DOCKET NO.: 51121-109WO2121 . The method of any one of claims 1-120, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the decitabine, or a pharmaceutically acceptable salt thereof, alone.

122. The method of any one of claims 2-121 , wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof.

123. The method of any one of claims 2-122, wherein (iv) the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin.

124. The method of any one of claims 2-123, wherein the anti-fungal agent is a CYP3A4 inhibitor.

125. The method of claim 124, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, or voriconazole.

126. The method of any one of claims 2-125, wherein the fungal infection is aspergillosis or candidiasis.

127. A method for treating hematologic cancer in a subject in need thereof, the method comprising administering to the subject (x) an anti-fungal agent, or a pharmaceutically acceptable salt thereof, and (y): (i) decitabine, or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

128. The method of claim 127, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (iii) the maintenance dose regimen of FHD 286, orPATENTATTORNEY DOCKET NO.: 51121-109WO2 a pharmaceutically acceptable salt thereof, and (i) the decitabine, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof.

129. The method of claim 127 or 128, wherein (x) the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin.

130. The method of any one of claims 127-129, wherein (x) the anti-fungal agent is a CYP3A4 inhibitor.131 . The method of claim 130, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, or voriconazole.

132. The method of any one of claims 127-131 , wherein the fungal infection is aspergillosis or candidiasis.

133. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject (x) an anti-fungal agent is administered as a (a) a loading dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, and following step (a), administering to the subject (b) a maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof, wherein (a) the loading dose regimen and (b) the maintenance dose regimen together are effective to reduce the risk of a fungal infection, and wherein the average daily dose during (a) the loading dose regimen is at least 2-fold higher than the average daily dose during (b) the maintenance dose regimen, and (y): (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

134. The method of claim 133, wherein (i) the decitabine is administered at a dose of 15 mg / m2by continuous intravenous transfusion over 3 hours repeated every 8 hours for 3 days.

135. The method of claim 133, wherein (i) the decitabine is administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days.

136. The method of any one of claims 133-135, wherein (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day.PATENTATTORNEY DOCKET NO.: 51121-109WO2137. The method of any one of claims 133-136, wherein (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day.

138. The method of any one of claims 133-137, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

139. The method of any one of claims 133-138, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least fourteen days.

140. The method of any one of claims 133-139, wherein (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 1 .5 mg per day, about 2.0 mg per day, subject about 2.5 mg per day, about 3.0 mg per day, about 3.5 mg per day, about 4.0 mg per day, about 4.5 mg per day, about 5.0 mg per day, about 5.5 mg per day, about 6.0 mg per day, about 6.5 mg per day, or about 7.0 mg per day.

141. The method of any one of claims 133-140, wherein (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 5.0 mg per day.

142. The method of any one of claims 133-141 , wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 2 weeks.

143. The method of any one of claims 133-142, wherein the average daily dose during (a) the loading dose regimen is at least 3-fold higher than the average daily dose during (b) the maintenance dose regimen.

144. The method of any one of claims 133-143, wherein (a) the loading dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs.

145. The method of any one of claims 133-144, wherein (b) the maintenance dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, once daily.

146. The method of any one of claims 133-145, wherein (a) the loading dose regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs, followed by (b) the maintenance dosePATENTATTORNEY DOCKET NO.: 51121-109WO2 regimen comprises administering to the subject between about 200 mg to 400 mg of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, once daily.

147. The method of any one of claims 133-146, wherein step (a) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 48 hours.

148. The method of any one of claims 133-147, wherein (a) the loading dose regimen comprises administering the anti-fungal agent, or a pharmaceutically acceptable salt thereof, at an average daily dose of about 600 mg.

149. The method of any one of claims 133-148, wherein step (b) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

150. The method of any one of claims 133-149, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 12 hours of each other.151 . The method of any one of claims 133-150, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 1 day of each other.

152. The method of any one of claims 133-151 , wherein decitabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.

153. The method of any one of claims 133-152, wherein (ii) the differentiation dose regimen of FHD 286 is administered orally.

154. The method of any one of claims 133-153, wherein (iii) the maintenance dose regimen of FHD 286 is administered orally.

155. The method of any one of claims 133-154, wherein (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered orally.

156. The method of any one of claims 133-154, wherein (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered intravenously.

157. The method of any one of claims 133-154, wherein (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally.

158. The method of any one of claims 133-154, wherein (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered intravenously.PATENTATTORNEY DOCKET NO.: 51121-109WO2159. The method of any one of claims 133-158, wherein (b) the maintenance dose regimen of the antifungal agent or a pharmaceutically acceptable salt thereof, is administered orally.

160. The method of any one of claims 133-158, wherein (b) the maintenance dose regimen of the antifungal agent or a pharmaceutically acceptable salt thereof, is intravenously.

161. The method of any one of claims 133-160, wherein the method comprises at least 21 days of treatment.

162. The method of any one of claims 133-160, wherein the method comprises at least 28 days of treatment.

163. The method of any one of claims 133-162, wherein the method comprises administering 1 , 2, or 3 cycles of decitabine.

164. The method of any one of claims 133-163, wherein the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

165. The method of any one of claims 133-164, wherein the method comprises administering 1 , 2, or 3 cycles of (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

166. The method of any one of claims 133-165, wherein the method comprises administering 1 , 2, or 3 cycles of (a) the loading dose regimen of an anti-fungal agent or a pharmaceutically acceptable salt and1 , 2, or 3 cycles of (b) the maintenance dose regimen of the anti-fungal agent or a pharmaceutically acceptable salt thereof.

167. The method of any one of claims 133-166, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.

168. The method of any one of claims 133-167, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (x) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.

169. The method of any one of claims 133-168, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the (iii) a maintenance dose regimen ofPATENTATTORNEY DOCKET NO.: 51121-109WO2FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject (i) the decitabine, or a pharmaceutically acceptable salt thereof and / or (x) the anti-fungal agent, or a pharmaceutically acceptable salt thereof.

170. The method of any one of claims 133-169, wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.171 . The method of any one of claims 133-170, wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.

172. The method of any one of claims 133-170, wherein the hematologic cancer is acute myeloid leukemia.

173. The method of any one of claims 133-170, wherein the hematologic cancer is myelodysplastic syndrome.

174. The method of any one of claims 133-173, wherein the hematologic cancer has an inv(3) mutation, a -7 / del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and / or a DNMT3A mutation.

175. The method of any one of claims 133-174, wherein the method inhibits cancer cell invasion or migration in a subject having a high risk of cancer cell invasion or migration.

176. The method of any one of claims 133-175, wherein the method suppresses metastatic progression of cancer.

177. The method of any one of claims 133-176, wherein the method suppresses metastatic colonization of cancer.

178. The method of any one of claims 133-177, wherein the method slows the spread of a migrating cancer in a subject having a high risk of the spread of the migrating cancer.

179. The method of any one of claims 133-178, wherein the method reduced the rate of tumor seeding of a cancer in a subject having a high risk of tumor seeding of a cancer.

180. The method of any one of claims 133-179, wherein the method reduces or treats metastatic nodule-forming of a cancer in a subject having a high risk of metastatic nodule-forming of a cancer.PATENTATTORNEY DOCKET NO.: 51121-109WO2181 . The method of any one of claims 133-180, wherein the method reduces metastatic risk of a cancer in a subject having a high metastatic risk.

182. The method of any one of claims 133-181 , wherein the method treats metastatic cancer in a subject having a high metastatic risk.

183. The method of any one of claims 133-182, wherein the method reduces tumor heterogeneity.

184. The method of any one of claims 133-183, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with FHD 286, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the decitabine, or a pharmaceutically acceptable salt thereof, alone.

185. The method of any one of claims 133-184, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof.

186. The method of any one of claims 133-185, wherein (iv) the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin.

187. The method of any one of claims 133-186, wherein the anti-fungal agent is a CYP3A4 inhibitor.

188. The method of claim 187, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, or voriconazole.

189. The method of any one of claims 133-188, wherein (x) the anti-fungal agent is isavuconazole.

190. The method of claim 189, wherein (a) the loading dose regimen comprises administering to the subject about 200 mg of the isavuconazole, every 8 hrs for 48 hrs, followed by (b) the maintenance dose regimen comprises administering to the subject between about 200 mg of the isavuconazole, once daily.

191. The method of any one of claims 133-190, wherein (a) the loading dose regimen of the isavuconazole, is administered orally or intravenously.

192. The method of any one of claims 133-190, wherein (b) the maintenance dose regimen of the isavuconazole, is administered orally, or intravenously.PATENTATTORNEY DOCKET NO.: 51121-109WO2193. The method of any one of claims 133-190, wherein (x) the anti-fungal agent is isavuconazonium sulfate.

194. The method of claim 191 , wherein (a) the loading dose regimen comprises administering to the subject about 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, every 8 hrs for 48 hrs, followed by (b) the maintenance dose regimen comprises administering to the subject between about 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, once daily.

195. The method of any one of claims 193-194, wherein (a) the loading dose regimen of the isavuconazonium sulfate, is administered orally or intravenously.

196. The method of any one of claims 193-195, wherein (b) the maintenance dose regimen of the isavuconazonium sulfate, is administered orally, or intravenously.

197. The method of any one of claims 133-196, wherein the fungal infection is aspergillosis or candidiasis.

198. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject (1) isavuconazole, or a pharmaceutically acceptable salt thereof, is administered as a (a) a loading dose regimen of about 200 mg of the isavuconazole or a pharmaceutically acceptable salt thereof, about every 8 hrs for about 48 hrs, and following step (a), administering to the subject (b) a maintenance dose regimen of about 200 mg of the isavuconazole, or a pharmaceutically acceptable salt thereof, once daily, and (i) decitabine, or a pharmaceutically acceptable salt thereof, and (ii) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein (i) the decitabine and (ii) the differentiation dose regimen together are effective to treat the hematologic cancer, and following step (ii), administering to the subject (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the (i) the decitabine, (ii) the differentiation dose regimen, and (iii) the maintenance dose regimen together are effective to treat the hematologic cancer, and wherein the average daily dose during (ii) the differentiation dose regimen is at least 1 .5-fold higher than the average daily dose during (ii) the maintenance dose regimen.

199. The method of claim 198, wherein (i) the decitabine is administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days.

200. The method of claim 198 or 199, wherein (ii) the differentiation dose regimen is administered daily to the subject administering to the subject about 7.5 mg per day.201 . The method of any one of claims 198-200, wherein (ii) the differentiation dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least fourteen days.PATENTATTORNEY DOCKET NO.: 51121-109WO2202. The method of any one of claims 198-201 , wherein (iii) the maintenance dose regimen is administered daily to the subject administering to the subject about 5.0 mg per day.

203. The method of any one of claims 198-202, wherein (iii) the maintenance dose regimen comprises administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least 2 weeks.

204. The method of any one of claims 198-203, wherein step (b) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one to fourteen days.

205. The method of any one of claims 198-204, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 12 hours of each other.

206. The method of any one of claims 198-205, wherein the final dose of (a) the loading dose regimen and the first dose of (b) the maintenance dose regimen are administered within 1 day of each other.

207. The method of any one of claims 198-206, wherein decitabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.

208. The method of any one of claims 198-207, wherein (ii) the differentiation dose regimen of FHD 286 is administered orally.

209. The method of any one of claims 198-208, wherein (iii) the maintenance dose regimen of FHD 286 is administered orally.

210. The method of any one of claims 198-209, wherein (a) the loading dose regimen of the isavuconazole, is administered orally or intravenously.

211. The method of any one of claims 198-210, wherein (b) the maintenance dose regimen of the isavuconazole, is administered orally, or intravenously.

212. The method of any one of claims 198-211 , wherein the pharmaceutically acceptable salt of isavuconazole is isavuconazonium sulfate.

213. The method of any one of claims 198-212, wherein the method comprises at least 21 days of treatment.

214. The method of any one of claims 198-212, wherein the method comprises at least 28 days of treatment.PATENTATTORNEY DOCKET NO.: 51121-109WO2215. The method of any one of claims 198-214, wherein the method comprises administering 1 , 2, or 3 cycles of decitabine.

216. The method of any one of claims 198-215, wherein the method comprises administering 1 , 2, or 3 cycles of (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and 1 , 2, or 3 cycles of (iii) the maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof.

217. The method of any one of claims 198-216, wherein the method comprises administering 1 , 2, or 3 cycles of (1) isavuconazole, or a pharmaceutically acceptable salt thereof.

218. The method of any one of claims 198-217, wherein the method comprises administering 1 , 2, or 3 cycles of (a) the loading dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof, and 1 , 2, or 3 cycles of (b) the maintenance dose regimen of isavuconazole, or a pharmaceutically acceptable salt thereof.

219. The method of any one of claims 198-218, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (1) isavuconazole, or a pharmaceutically acceptable salt thereof, are administered within 12 hours of each other.

220. The method of any one of claims 198-219, wherein (i) the decitabine, or a pharmaceutically acceptable salt thereof, (ii) the differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and (1) isavuconazole, or a pharmaceutically acceptable salt thereof, are administered within 1 day of each other.221 . The method of any one of claims 198-220, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the (iii) a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, without further administering to the subject (i) the decitabine, or a pharmaceutically acceptable salt thereof and / or (1) isavuconazole, or a pharmaceutically acceptable salt thereof.

222. The method of any one of claims 198-221 , wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.

223. The method of any one of claims 198-221 , wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.PATENTATTORNEY DOCKET NO.: 51121-109WO2224. The method of any one of claims 198-221 , wherein the hematologic cancer is acute myeloid leukemia.

225. The method of any one of claims 198-221 , wherein the hematologic cancer is myelodysplastic syndrome.

226. The method of any one of claims 198-225, wherein the hematologic cancer has an inv(3) mutation, a -7 / del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and / or a DNMT3A mutation.

227. The method of any one of claims 198-226, wherein the method inhibits cancer cell invasion or migration in a subject having a high risk of cancer cell invasion or migration.

228. The method of any one of claims 198-227, wherein the method suppresses metastatic progression of cancer.

229. The method of any one of claims 198-228, wherein the method suppresses metastatic colonization of cancer.

230. The method of any one of claims 198-229, wherein the method slows the spread of a migrating cancer in a subject having a high risk of the spread of the migrating cancer.231 . The method of any one of claims 198-230, wherein the method reduced the rate of tumor seeding of a cancer in a subject having a high risk of tumor seeding of a cancer.

232. The method of any one of claims 198-231 , wherein the method reduces or treats metastatic nodule-forming of a cancer in a subject having a high risk of metastatic nodule-forming of a cancer.

233. The method of any one of claims 198-232, wherein the method reduces metastatic risk of a cancer in a subject having a high metastatic risk.

234. The method of any one of claims 198-233, wherein the method treats metastatic cancer in a subject having a high metastatic risk.

235. The method of any one of claims 198-234, wherein the method reduces tumor heterogeneity.

236. The method of any one of claims 198-235, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the FHD 286, or a pharmaceutically acceptable salt thereof and decitabine, or a pharmaceutically acceptable salt thereof, and isavuconazole, or a pharmaceutically acceptable salt thereof.PATENTATTORNEY DOCKET NO.: 51121-109WO2237. The method of any one of claims 198-236, wherein the fungal infection is aspergillosis or candidiasis.

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