Treatment of acute myeloid leukemia (AML) with venetoclax failure

Abstract

Provided herein are various regimens for treating acute myeloid leukemia (AML) in subjects (e.g, patients) who have undergone one or more prior anti-AML therapies involving venetoclax, and have shown disease progression after the one or more prior therapies. The treatment regimens disclosed herein involve alvocidib, either as a monotherapy, or in combination with cytarabine or a hypomethylating agent, such as decitabine or azacitidine. The treatment regimens disclosed herein do not involve combination therapy of alvocidib with venetoclax.

Claims

1. A method for treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering an effective amount of alvocidib to the subject in the absence of venetoclax, wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax and a hypomethylating agent.

2. The method of claim 1, wherein the hypomethylating agent is azacitidine, decitabine, or azacitidine and decitabine.

3. The method of claim 1, wherein the one or more prior therapies comprising venetoclax and a hypomethylating agent is an induction therapy.

4. The method of claim 1, wherein the alvocidib is a compound having the structure of Formula (I): ##STR00014## or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein the alvocidib is a compound having the structure of Formula (I-b): ##STR00015## or a pharmaceutically acceptable salt thereof.

6. A method for treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising, in the absence of venetoclax: (i) administering to the subject an effective amount of alvocidib in a first course of treatment; (ii) administering to the subject an effective amount of cytarabine in a second course of treatment; and (iii) administering to the subject an effective amount of alvocidib in a third course of treatment; wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax and a hypomethylating agent.

7. The method of claim 1, comprising administering to the subject an effective amount of alvocidib in the absence of an additional chemotherapeutic agent for AML, wherein the subject has refractory, resistant, or relapsed AML after an induction therapy comprising venetoclax and a hypomethylating agent.

8. The method of claim 7, wherein the alvocidib is a compound having the structure of Formula (I): ##STR00016## or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein: from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on day 1 of a 28-day treatment cycle; and from about 40 mg/m.sup.2 to about 80 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on days 8 and 15 of the 28-day treatment cycle.

10. The method of claim 7, comprising administering to the subject, in the absence of an additional chemotherapeutic agent for AML: from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 of a compound having the structure of Formula (I): ##STR00017## or a pharmaceutically acceptable salt thereof, by intravenous bolus on day 1 of a 28-day treatment cycle; and from about 40 mg/m.sup.2 to about 80 mg/m.sup.2 of the compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, by intravenous bolus on days 8 and 15 of the 28-day treatment cycle, wherein the subject has refractory, resistant, or relapsed AML after an induction therapy comprising venetoclax and azacitidine or venetoclax and decitabine.

11. The method of claim 10, wherein: about 25 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on day 1 of a 28-day treatment cycle; and about 50 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on days 8 and 15 of the 28-day treatment cycle.

12. The method of claim 1, comprising administering to the subject an effective amount of alvocidib and low-dose cytarabine in the absence of an additional chemotherapeutic agent for AML, wherein the subject has refractory, resistant, or relapsed AML after an induction therapy comprising venetoclax and a hypomethylating agent.

13. The method of claim 12, wherein the alvocidib is a compound having the structure of Formula (I): ##STR00018## or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein: from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on day 1 of a 28-day treatment cycle; and from about 40 mg/m.sup.2 to about 80 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on day 15 of the 28-day treatment cycle.

15. The method of claim 14, wherein: from about 10 mg/m.sup.2 to about 100 mg/m.sup.2 cytarabine is administered per day by injection on days 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of the 28-day treatment cycle.

16. The method of claim 12, comprising administering to the subject, in the absence of an additional chemotherapeutic agent for AML: from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 of a compound having the structure of Formula (I): ##STR00019## or a pharmaceutically acceptable salt thereof, by intravenous bolus on day 1 of a 28-day treatment cycle; from about 10 mg/m.sup.2 to about 100 mg/m.sup.2 cytarabine, per day by injection on days 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of the 28-day treatment cycle; and from about 40 mg/m.sup.2 to about 80 mg/m.sup.2 of the compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, by intravenous bolus on days 8 and 15 of the 28-day treatment cycle, wherein the subject has refractory, resistant, or relapsed AML after an induction therapy comprising venetoclax and azacitidine or venetoclax and decitabine.

17. The method of claim 16, wherein: about 25 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on day 1 of a 28-day treatment cycle; and about 50 mg/m.sup.2 of the alvocidib is administered by intravenous bolus on day 15 of the 28-day treatment cycle.

18. The method of claim 16, wherein: about 20 mg/m.sup.2 cytarabine is administered per day by injection on days 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of the 28-day treatment cycle.

19. The method of claim 1, wherein the subject is a human.

20. A method for inhibiting development of tumor lysis syndrome (TLS) in a subject; reducing the severity of TLS in a subject decreasing mortality from TLS in subjects; reducing the incidence of TLS in subjects; preventing TLS in a subject; or treating AML in a subject without high risk for developing TLS, the method comprising administering alvocidib to the subject at a first dose of from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 in the absence of venetoclax, wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax.

Description

EXAMPLE EMBODIMENTS

(1) A1. A method for treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising: administering an effective amount of alvocidib, to the subject in the absence of venetoclax, wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax.

(2) A2. The method of claim A1, wherein the one or more prior therapies further comprise one or more other therapeutic agents for treating AML.

(3) A3. The method of claim A2, wherein the one or more other therapeutic agents for treating AML is azacitidine, decitabine, or a combination thereof.

(4) A4. The method of any one of claims A1-A3, wherein the method comprises the alvocidib as a sole treatment agent for AML.

(5) A5. The method of any one of claims A1-A4, wherein the alvocidib is a compound having the structure of Formula (I):

(6) ##STR00008##
or a pharmaceutically acceptable salt thereof.

(7) A6. The method of any one of claims A1-A4, wherein the alvocidib is a compound having the structure of Formula (I-b):

(8) ##STR00009##
or a pharmaceutically acceptable salt thereof.

(9) A7. The method of any one of claims A1-A6, wherein the subject has refractory AML, and the one or more prior therapies comprise up to 2 cycles of venetoclax treatment.

(10) A8. The method of any one of claims A1-A6, wherein the subject has relapsed AML after the one or more prior therapies.

(11) A9. The method of claim A8, wherein the subject has relapsed AML, after a first complete remission (CR1) period of about 90 days to about 18 months.

(12) A10. The method of any one of claims A1-A9, wherein the effective amount of the alvocidib is from about 20 mg/m.sup.2 to about 100 mg/m.sup.2 once per week.

(13) All. The method of any one of claims A1-A10, wherein the effective amount of the alvocidib is about 25 mg/m.sup.2 or about 50 mg/m.sup.2 once per week.

(14) A12. The method of any one of claims A1-A11, wherein the alvocidib is administered to the subject at a dose of from about 20 mg/m.sup.2 to about 100 mg/m.sup.2 as an intravenous bolus in about 15 minutes to about an hour once every week.

(15) A13. The method of any one of claims A1-A10, wherein the alvocidib is administered to the subject at a dose of from about 25 mg/m.sup.2 to about 50 mg/m.sup.2 as an intravenous bolus in about 30 minutes.

(16) A14. The method of claim A13, wherein the alvocidib is administered to the subject at a dose of about 25 mg/m.sup.2 or about 50 mg/m.sup.2.

(17) A15. The method of any one of claims A1-A14, wherein alvocidib is administered to the subject once every week for about 1 to about 4 consecutive weeks, followed by a drug holiday period of about 1 to about 3 weeks as a treatment cycle.

(18) A16. The method of claim A15, wherein the alvocidib is administered to the subject once every week for 3 consecutive weeks followed by a drug holiday period of 1 week as a treatment cycle.

(19) A17. The method of any one of claims A1-A16, wherein the method comprises 1-8 of the treatment cycles.

(20) A18. The method of any one of claims A1-A16, wherein the method comprises a plurality of the treatment cycles until the treatment shows substantially no benefit on the subject.

(21) A19. The method of any one of claims A15-A18, wherein each treatment cycle comprises: (i) administering alvocidib to the subject at a dose of from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 as an intravenous bolus in about 15 minutes to about an hour, and (ii) about one week after step (i), administering alvocidib to the subject at a dose of from about 40 mg/m.sup.2 to about 80 mg/m.sup.2 as an intravenous bolus in about 15 minutes to about an hour once every week for 2-4 weeks, followed by a drug holiday period of about 2 to about 4 weeks.

(22) A20. The method of any one of claims A15-A19, wherein each treatment cycle consists of 4 weeks, and comprises: (i) administering alvocidib to the subject at a dose of about 25 mg/m.sup.2 as an intravenous bolus in about 30 minutes on the first day of the first week, and (ii) administering alvocidib to the subject at a dose of about 50 mg/m.sup.2 as an intravenous bolus in about 30 minutes on the first day of the second week and the first day of the third week, followed by a drug holiday period of about 1 week.

(23) A21. The method of any one of claims A15-A20, wherein the method comprises 2-6 treatment cycles.

(24) A22. The method of claim A21, wherein the method comprises 3-5 treatment cycles.

(25) A23. The method of any one of claims A1-A22, further comprising terminating administration of alvocidib in a subject who fails to achieve at least about a 20% reduction in leukemia blast count.

(26) A24. The method of any one of claims A1-A23, further comprising administering to the subject an effective amount of acyclovir, trimethoprim, sulfamethoxazole, or a combination thereof.

(27) A25. The method of any one of claims A1-A24, further comprising administering an effective amount of ciprofloxacin to the subject who has neutropenia.

(28) A26. The method of any one of claims A1-A25, wherein the subject is free of a treatment comprising a granulocyte colony stimulating factor.

(29) A27. The method of any one of claims A1-A26, wherein the subject is MCL-1 dependent.

(30) A28. The method of any one of claims A1-A27, wherein the subject is identified as MCL-1 dependent.

(31) A29. The method of claim A28, wherein the subject is identified as MCL-1 dependent by examining a bone marrow sample of the subject.

(32) A30. The method of claim A6, wherein the compound of Formula (I-b), or pharmaceutically acceptable salt thereof, is administered to the subject orally.

(33) A31. The method of any one of claims A1-A30, wherein the subject is measurable residual disease (MRD)-positive prior to being administered the alvocidib.

(34) A32. The method of any one of claims A1-A31, wherein the subject is measurable residual disease (MRD)-negative after being administered the alvocidib.

(35) A33. The method of any one of claims A1-A32, further comprising detecting the measurable residual disease (MRD) status of the subject.

(36) A34. The method of claim A33, wherein the MRD status of the subject is detected prior to administering the alvocidib to the subject.

(37) A35. The method of claim A33, wherein the MRD status of the subject is detected after administering the alvocidib to the subject.

(38) A36. The method of any one of claims A33-A35, wherein the MRD status of the subject is detected prior to and after administering the alvocidib to the subject.

(39) A37. The method of any one of claims A1-A36, further comprising terminating administration of the alvocidib to the subject if the subject is determined to be measurable residual disease (MRD)-negative.

(40) B1. A method for treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising, in the absence of venetoclax:

(41) (i) administering to the subject an effective amount of alvocidib in a first course of treatment;

(42) (ii) administering to the subject an effective amount of cytarabine in a second course of treatment; and

(43) (iii) administering to the subject an effective amount of alvocidib in a third course of treatment;

(44) wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax.

(45) B2. The method of claim B1, wherein the one or more prior therapies further comprise one or more other therapeutic agents for treating AML.

(46) B3. The method of claim B2, wherein the one or more other therapeutic agents comprise azacitidine, decitabine, or a combination thereof.

(47) B4. The method of any one of claims B1-B3, wherein the alvocidib is a compound having the structure of Formula (I):

(48) ##STR00010##
or a pharmaceutically acceptable salt thereof.

(49) B5. The method of any one of claims B1-B3, wherein the alvocidib is a compound having the structure of Formula (I-b):

(50) ##STR00011##
or a pharmaceutically acceptable salt thereof.

(51) B6. The method of any one of claims B1-B5, wherein step (ii) is performed after step (i), and step (iii) is performed after step (ii).

(52) B7. The method of any one of claims B1-B6, wherein the effective amount of the alvocidib in the first course of treatment differs from the effective amount of the alvocidib in the third course of treatment.

(53) B8. The method of any one of claims B1-B7, wherein the effective amount of the alvocidib in the first course of treatment is from about 10 mg/m.sup.2 to about 50 mg/m.sup.2 per day.

(54) B9. The method of claim B8, wherein the effective amount of the alvocidib in the first course of treatment is about 25 mg/m.sup.2 per day.

(55) B10. The method of any one of claims B1-B9, wherein the first course of treatment consists of about 1 to about 4 days.

(56) B11. The method of claim B10, wherein the first course of treatment consists of one day or two days.

(57) B12. The method of any one of claims B1-B11, where the effective amount of the cytarabine in the second course of treatment is from about 10 mg/m.sup.2 to about 100 mg/m.sup.2 per day.

(58) B13. The method of claim B12, wherein the effective amount of the cytarabine in the second course of treatment is about 20 mg/m.sup.2 per day.

(59) B14. The method of any one of claims B1-B13, wherein the second course of treatment consists of 8-12 days.

(60) B15. The method of claim B14, wherein the second course of treatment consists of 10 days.

(61) B16. The method of any one of claims B1-B15, wherein the effective amount of the alvocidib in the third course of treatment is from about 25 mg/m.sup.2 to about 100 mg/m.sup.2 per day.

(62) B17. The method of claim B16, wherein the effective amount of the alvocidib in the third course of treatment is about 50 mg/m.sup.2 per day.

(63) B18. The method of any one of claims B1-B17, wherein the third course of treatment consists of 1-3 days.

(64) B19. The method of claim B18, wherein the third course of treatment consists of 1 day or 2 days.

(65) B20. The method of any one of claims B1-B19, wherein the first course of treatment consists of 1 day and is followed by a first drug holiday period of 1 day, prior to the commencement of the second course of treatment.

(66) B21. The method of any one of claims B1-B20, wherein the second course of treatment consists of 10 days and is followed by a second drug holiday period of 2 days, prior to the commencement of the third course of treatment.

(67) B22. The method of any one of claims B1-B21, wherein the third course of treatment consists of 1 day and is followed by a third drug holiday period of about 13 days.

(68) B23. The method of any one of claims B1-B22, wherein the method comprises multiple treatment cycles, and each treatment cycle comprises the first course of treatment, the second course of treatment, and the third course of treatment, and is repeated every 28 days.

(69) B24. The method of claim B23, wherein each treatment cycle comprises:

(70) (i) administering the alvocidib to the subject at a daily dose of from about 10 mg/m.sup.2 to about 50 mg/m.sup.2 as an intravenous bolus in about 15 minutes to about one hour for about 1 to about 3 days, followed by a first drug holiday period of about 1 to about 3 days;

(71) (ii) administering the cytarabine to the subject by subcutaneous injection at a daily dose of from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 for 8-12 days, followed by a second drug holiday period of 1-3 days, and

(72) (iii) administering the alvocidib to the subject at a daily dose of from about 25 mg/m.sup.2 to about 100 mg/m.sup.2 as an intravenous bolus in about 15 minutes to about one hour for about 1 to about 3 days, followed by a third drug holiday period of about 12 to about 14 days.

(73) B25. The method of claim B24, wherein each treatment cycle comprises:

(74) (i) administering the alvocidib to the subject at a daily dose of about 25 mg/m.sup.2 as an intravenous bolus in about 30 minutes for one day in the first course of treatment, followed by the first drug holiday period of one day;

(75) (ii) administering the cytarabine to the subject by subcutaneous injection at a daily dose of about 20 mg/m.sup.2 for 10 days in the second course of treatment, followed by a second drug holiday period of 2 days; and

(76) (iii) administering the alvocidib to the subject at a daily dose of about 50 mg/m.sup.2 as intravenous bolus in about 30 minutes for 1 day in the third course of treatment, followed by the third drug holiday period of about 13 days.

(77) B26. The method of claim B24 or B25, wherein each treatment cycle consists of 28 days, and comprises:

(78) (i) administering the alvocidib to the subject at a daily dose of about 25 mg/m.sup.2 as an intravenous bolus in about 30 minutes on Day 1, followed by the first drug holiday period on Day 2;

(79) (ii) administering the cytarabine to the subject by subcutaneous injection at a daily dose of about 20 mg/m.sup.2 on Days 3-12, followed by the second drug holiday period on Days 13-14; and

(80) (iii) administering the alvocidib to the subject at a daily dose of about 50 mg/m.sup.2 as an intravenous bolus in about 30 minutes on Day 15, followed by the third drug holiday period on Days 16-28.

(81) B27. The method of any one of claims B1-B5, wherein step (iii) is performed after step (i), and step (ii) is performed after step (iii).

(82) B28. The method of claim B27, wherein steps (i), (ii), and (iii) are separated by one or more drug holiday periods.

(83) B29. The method of claim B27 or claim B28, wherein the effective amount of alvocidib in the first course of treatment is from about 10 mg/m.sup.2 to about 50 mg/m.sup.2 per day.

(84) B30. The method of claim B29, wherein the effective amount of alvocidib in the first course of treatment is about 25 mg/m.sup.2.

(85) B31. The method of any one of claims B27-B29, wherein the first course of treatment consists of about 1-4 days.

(86) B32. The method of claim B31, wherein the first course of treatment consists of one day or two days.

(87) B33. The method of any one of claims B27-B32, wherein the effective amount of the alvocidib in the third course of treatment is from about 25 mg/m.sup.2 to about 100 mg/m.sup.2 per day.

(88) B34. The method of claim B33, wherein the effective amount of the alvocidib in the third course of treatment is about 50 mg/m.sup.2 per day.

(89) B35. The method of any one of claims B27-B34, wherein the third course of treatment consists of 1-3 days.

(90) B36. The method of claim B35, wherein the third course of treatment consists of 1 day or 2 days.

(91) B37. The method of any one of claims B27-B36, wherein the first course of treatment consists of 1 day and the third course of treatment consists of 2 days, or wherein the first course of treatment consists of 2 days and the third course of treatment consists of 1 day.

(92) B38. The method of any one of claims B27-B37, wherein the effective amount of the cytarabine in the second course of treatment is from about 10 mg/m.sup.2 to about 100 mg/m.sup.2 per day.

(93) B39. The method of claim B38, wherein the effective amount of the cytarabine in the second course of treatment is about 20 mg/m.sup.2 per day.

(94) B40. The method of claim B38 or B39, wherein the second course of treatment consists of 8-12 days.

(95) B41. The method of claim B40, wherein the second course of treatment consists of 10 days.

(96) B42. The method of any one of claims B1-B41, wherein the effective amount of cytarabine in the second course of treatment is 20 mg/m.sup.2 once or twice daily for 10 days.

(97) B43. The method of any one of claims B1-B42, wherein the effective amount of cytarabine in the second course of treatment is 20 mg/m.sup.2 daily, which is divided into two doses, for 4 days, and wherein the two doses are administered to the subject 12 hours apart.

(98) B44. The method of claim B43, wherein the cytarabine is administered to the subject 2 days per week.

(99) B45. The method of any one of claims B1-B42, wherein the effective amount of the cytarabine in the second course of treatment is 20 mg/m.sup.2 twice daily for 10 days.

(100) B46. The method of any one of claims B1-B41, wherein the effective amount of cytarabine in the second course of treatment is 40 mg/m.sup.2 once daily or 20 mg/m.sup.2 twice daily for 10 days.

(101) B47. The method of any one of claims B1-B46, wherein the alvocidib in the first course of treatment, in the third course of treatment, or both is administered by intravenous infusion.

(102) B48. The method of claim B47, wherein the alvocidib in the first course of treatment, in the third course of treatment, or both is administered as a 15-minute to one-hour intravenous bolus.

(103) B49. The method of claim B48, wherein the alvocidib in the first course of treatment, in the third course of treatment, or both is administered as a 30-minute intravenous bolus.

(104) B50. The method of any one of claims B1-B49, wherein the cytarabine in the second course of treatment is administered by injection.

(105) B51. The method of claim B50, wherein the cytarabine in the second course of treatment is administered by subcutaneous injection.

(106) B52. The method of any one of claims B1-B51, further comprising administering to the subject an effective amount of an intravenous hydration fluid, allopurinol, a phosphate binder, or a combination thereof, at least prior to the first dose of alvocidib.

(107) B53. The method of any one of claims B1-B52, further comprising administering to the subject an effective amount of an antibiotic, an anti-viral agent, an anti-fungal agent, or a combination thereof.

(108) B54. The method of any one of claims B1-B53, wherein the subject is MCL-1 dependent.

(109) B55. The method of any one of claims B1-B54, wherein the subject is identified as MCL-1 dependent.

(110) B56. The method of claim B55, wherein the subject is identified as MCL-1 dependent by examining a bone marrow sample of the subject.

(111) B57. The method of claim B5, wherein the compound of Formula (I-b), or pharmaceutically acceptable salt thereof, is administered to the subject orally.

(112) B58. The method of any one of claims B1-B57, wherein the subject is measurable residual disease (MRD)-positive prior to being administered the first, second and third courses of treatment.

(113) B59. The method of any one of claims B1-B58, wherein the subject is measurable residual disease (MRD)-negative after being administered the first, second and third courses of treatment.

(114) B60. The method of any one of claims B1-B59, further comprising detecting the measurable residual disease (MRD) status of the subject.

(115) B61. The method of claim B60, wherein the MRD status of the subject is detected prior to administering the first, second and third courses of treatment to the subject.

(116) B62. The method of claim B60, wherein the MRD status of the subject is detected after administering the first, second and third courses of treatment to the subject.

(117) B63. The method of any one of claims B60-B62, wherein the MRD status of the subject is detected prior to and after administering the first, second and third courses of treatment to the subject.

(118) B64. The method of any one of claims B1-B63, further comprising terminating administration of at least the first and third courses of treatment to the subject if the subject is determined to be measurable residual disease (MRD)-negative.

(119) C1. A method for treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising, in the absence of venetoclax: (i) administering to the subject an effective amount of decitabine or azacitidine in a first course of treatment; and (ii) administering to the subject an effective amount of alvocidib in a second course of treatment;

(120) wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax.

(121) C2. The method of claim C1, wherein the one or more prior therapies further comprise one or more other therapeutic agents for treating AML.

(122) C3. The method of claim C2, wherein the one or more other therapeutic agents comprise azacitibine, decitabine, or a combination thereof.

(123) C4. The method of any one of claims C1-C3, wherein the alvocidib is a compound having the structure of Formula (I):

(124) ##STR00012##
or a pharmaceutically acceptable salt thereof.

(125) C5. The method of any one of claims C1-C4, wherein the alvocidib is a compound having the structure of Formula (I-b):

(126) ##STR00013##
or a pharmaceutically acceptable salt thereof.

(127) C6. The method of any one of claims C1-C5, wherein the effective amount of the alvocidib is from about 20 mg/m.sup.2 to about 150 mg/m.sup.2 once per day.

(128) C7. The method of claim C6, wherein the alvocidib is administered to the subject as a 15-minute to one-hour intravenous bolus.

(129) C8. The method of claim C6, wherein a portion of the alvocidib is administered to the subject as a 15-minute to one-hour intravenous bolus, and the remaining alvocidib is administered to the subject by intravenous infusion in about 3 to about 6 hours.

(130) C9. The method of any one of claims C1-C8, wherein the effective amount of the decitabine is about 15 mg/m.sup.2 to about 40 mg/m.sup.2 once every day.

(131) C10 The method of any one of claims C1-C9, wherein the decitabine is administered to the subject by intravenous infusion.

(132) C11. The method of any one of claims C1-C10, wherein the effective amount of azacitidine is from about 50 mg/m.sup.2 to about 100 mg/m.sup.2 once every day.

(133) C12. The method of any one of claims C1-C11, wherein the azacitidine is administered to the subject by intravenous injection or subcutaneous injection.

(134) C13. The method of any one of claims C1-C12, wherein the method comprises one or more treatment cycles, each treatment cycle comprising: (i) administering to the subject (a) the decitabine at from about 15 mg/m.sup.2 to about 40 mg/m.sup.2 once every day for 3-10 days, or (b) the azacitidine at from about 50 mg/m.sup.2 to about 100 mg/m.sup.2 once every day for 3-10 days; followed by a drug holiday period of about 1 to about 4 days; and (ii) administering to the subject the alvocidib at a dose of about 20 mg/m.sup.2 to about 100 mg/m.sup.2 once per day for 1-3 days.

(135) C14. The method of claim C13, wherein each treatment cycle consists of 28 days, and comprises: (i) administering to the subject the decitabine at about 20 mg/m.sup.2 once every day on Days 1-5; followed by a first drug holiday period on Days 6 and 7; and (ii) administering to the subject the alvocidib at a dose of from about 20 mg/m.sup.2 to about 100 mg/m.sup.2 on Day 8; followed by a second drug holiday period on Days 9-28.

(136) C15. The method of claim C13, wherein each treatment cycle consists of 28 days, and comprises: (i) administering to the subject the azacitidine at about 75 mg/m.sup.2 once every day on Days 1-5; followed by a first drug holiday period on Days 6 and 7; and (ii) administering to the subject the alvocidib at a dose of from about 20 mg/m.sup.2 to about 100 mg/m.sup.2 on Day 8; followed by a second drug holiday period on Days 9-28.

(137) C16. The method of any one of claims C1-C15, wherein the subject is MCL-1 dependent.

(138) C17. The method of any one of claims C1-C16, wherein the subject is identified as MCL-1 dependent.

(139) C18. The method of claim C17, wherein the subject is identified as MCL-1 dependent by examining a bone marrow sample of the subject.

(140) C19. The method of claim C5, wherein the compound of Formula (I-b), or pharmaceutically acceptable salt thereof, is administered to the subject orally.

(141) C20. The method of any one of claims C1-C19, wherein the subject is measurable residual disease (MRD)-positive prior to being administered the second course of treatment.

(142) C21. The method of any one of claims C1-C20, wherein the subject is measurable residual disease (MRD)-negative after being administered the second course of treatment.

(143) C22. The method of any one of claims C1-C21, further comprising detecting the measurable residual disease (MRD) status of the subject.

(144) C23. The method of claim C22, wherein the MRD status of the subject is detected prior to administering the second course of treatment to the subject.

(145) C24. The method of claim C22, wherein the MRD status of the subject is detected after administering the second course of treatment to the subject.

(146) C25. The method of any one of claims C22-C24, wherein the MRD status of the subject is detected prior to and after administering the second course of treatment to the subject.

(147) C26. The method of any one of claims C1-C25, further comprising terminating administration of at least the second course of treatment to the subject if the subject is determined to be measurable residual disease (MRD)-negative.

(148) D1. A method for inhibiting development of tumor lysis syndrome (TLS) in a subject having a hematological cancer, the method comprising administering to the subject alvocidib and, optionally, cytarabine, in the absence of venetoclax, following the conditions set forth in any one of the preceding claims, wherein the subject has refractory, resistant, or relapsed hematological cancer after one or more prior therapies, at least one of which comprises venetoclax.

(149) D2. A method of reducing the severity of tumor lysis syndrome (TLS) in a subject having a hematological cancer and being treated with alvocidib, the method comprising administering to the subject an effective amount of alvocidib and, optionally, cytarabine, in the absence of venetoclax, following the conditions set forth in any one of the preceding claims, wherein the subject has refractory, resistant, or relapsed hematological cancer after one or more prior therapies, at least one of which comprises venetoclax.

(150) D3. A method of treating tumor lysis syndrome (TLS) in a subject having a hematological cancer and being treated with alvocidib, the method comprising administering to the subject an effective amount of alvocidib and, optionally, cytarabine, in the absence of venetoclax, following the conditions set forth in any one of the preceding claims, wherein the subject has refractory, resistant, or relapsed hematological cancer after one or more prior therapies, at least one of which comprises venetoclax.

(151) D4. A method of decreasing mortality from tumor lysis syndrome (TLS) in a subject having a hematological cancer and being treated with alvocidib, the method comprising administering to the subject an effective amount of alvocidib and, optionally, cytarabine, in the absence of venetoclax, following the conditions set forth in any one of the preceding claims, wherein the subject has refractory, resistant, or relapsed hematological cancer after one or more prior therapies, at least one of which comprises venetoclax.

(152) D5. A method of reducing the incidence of tumor lysis syndrome (TLS) in a subject having a hematological cancer and being treated with alvocidib, the method comprising administering to the subject an effective amount of alvocidib and, optionally, cytarabine, in the absence of venetoclax, following the conditions set forth in any one of the preceding claims, wherein the subject has refractory, resistant, or relapsed hematological cancer after one or more prior therapies, at least one of which comprises venetoclax.

(153) D6. A method of preventing tumor lysis syndrome (TLS) in a subject having a hematological cancer and being treated with alvocidib, the method comprising administering to the subject an effective amount of alvocidib and, optionally, cytarabine, in the absence of venetoclax, following the conditions set forth in any one of the preceding claims, wherein the subject has refractory, resistant, or relapsed hematological cancer after one or more prior therapies, at least one of which comprises venetoclax.

(154) D7. A method of treating a hematological cancer in a subject without high risk for developing tumor lysis syndrome (TLS), the method comprising administering to the subject an effective amount of alvocidib and, optionally, cytarabine, in the absence of venetoclax, following the conditions set forth in any one of the preceding claims, wherein the subject has refractory, resistant, or relapsed hematological cancer after one or more prior therapies, at least one of which comprises venetoclax.

(155) D8. The method of any one of claims D1-D7, wherein the hematological cancer is acute myeloid leukemia (AML).

(156) D9. The method of any one of claims D1-D8, wherein the subject is identified as at risk for developing TLS.

(157) D10. The method of any one of claims D1-D9, wherein the one or more prior therapies further comprise one or more other therapeutic agents for treating AML.

(158) D11. The method of claim D10, wherein the one or more other therapeutic agents comprise azacitidine, decitabine, or a combination thereof.

(159) E1. A method for treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising, in the absence of venetoclax:

(160) (i) administering to the subject an effective amount of alvocidib in a first course of treatment;

(161) (ii) administering to the subject cytarabine at a daily dose of about 500 mg/m.sup.2 to about 3 g/m.sup.2 in a second course of treatment; and

(162) (iii) administering to the subject an effective amount of alvocidib in a third course of treatment;

(163) wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax.

(164) E2. The method of claim E1, wherein the one or more prior therapies further comprise one or more other therapeutic agents.

(165) E3. The method of claim E2, wherein the one or more other therapeutic agents comprise decitabine, azacitidine, or a combination thereof.

(166) E4. The method of any one of claims E1-E3, wherein the effective amount of the cytarabine in the second course of treatment is about 1 g/m.sup.2 per day.

(167) E5. The method of any one of claims E1-E4, wherein the second course of treatment consists of 3-8 days.

(168) E6. The method of claim E5, wherein the second course of treatment consists of 5 days.

(169) E7. The method of any one of claims E1-E6, wherein step (i) and step (iii) are performed as set forth in any one of claims B7-B11, B17-B22, B29-B36, and B46-B48.

(170) E8. The method of any one of claims E1-E7, wherein the subject is MCL-1 dependent.

(171) E9. The method of any one of claims E1-E8, wherein the subject is identified as MCL-1 dependent.

(172) E10. The method of claim E9, wherein the subject is identified as MCL-1 dependent by examining a bone marrow sample of the subject.

(173) E11. The method of any one of claims E1-E10, wherein the subject is measurable residual disease (MRD)-positive prior to being administered the first, second and third courses of treatment.

(174) E12. The method of any one of claims E1-11, wherein the subject is measurable residual disease (MRD)-negative after being administered the first, second and third courses of treatment.

(175) E13. The method of any one of claims E1-E12, further comprising detecting the measurable residual disease (MRD) status of the subject.

(176) E14. The method of claim E13, wherein the MRD status of the subject is detected prior to administering the first, second and third courses of treatment to the subject.

(177) E15. The method of claim E13, wherein the MRD status of the subject is detected after administering the first, second and third courses of treatment to the subject.

(178) E16. The method of any one of claims E13-E15, wherein the MRD status of the subject is detected prior to and after administering the first, second and third courses of treatment to the subject.

(179) E17. The method of any one of claims E1-E16, further comprising terminating administration of at least the first and third courses of treatment to the subject if the subject is determined to be measurable residual disease (MRD)-negative.

(180) F1. A method for treating acute myeloid leukemia (AML) in a subject in need thereof, the method comprising, in the absence of venetoclax and mitoxantrone: (i) administering to the subject an effective amount of alvocidib in a first course of treatment; and (ii) administering to the subject an effective amount of cytarabine in a second course of treatment;

(181) wherein the subject has refractory, resistant, or relapsed AML after one or more prior therapies, at least one of which comprises venetoclax.

(182) F2. The method of claim F1, wherein the one or more prior therapies further comprise one or more other therapeutic agents for treating AML.

(183) F3. The method of claim F2, wherein the one or more other therapeutic agents comprise azacitidine, decitabine, or a combination thereof.

(184) F4. The method of any one of claims F1-F3, wherein step (i) is performed following step (ii).

(185) F5. The method of any one of claims F1-F4, wherein the effective amount of cytarabine in the second course of treatment is from about 10 mg/m.sup.2 to about 100 mg/m.sup.2 per day.

(186) F6. The method of claim F5, wherein the effective amount of cytarabine in the second course of treatment is about 20 mg/m.sup.2 per day.

(187) F7. The method of any one of claims F1-F6, wherein the second course of treatment consists of 8-12 days.

(188) F8. The method of any one of claims F1-F7, wherein step (i) comprises administering to the subject the alvocidib at a dose of from about 25 mg/m.sup.2 to about 100 mg/m.sup.2 per day for about 1-4 days.

(189) F9. The method of claim F8, wherein alvocidib is administered to the subject at a dose of 50 mg/m.sup.2 per day as an intravenous bolus in about 30 minutes once every day for 3 days.

(190) F10. The method of any one of claims F1-F3, wherein step (i) is performed before step (ii).

(191) F11. The method of claim F10, wherein step (i) comprises administering the alvocidib to the subject at a daily dose of from about 80 mg/m.sup.2 to about 120 mg/m.sup.2.

(192) F12. The method of claim F11, wherein in step (i), alvocidib is administered to the subject once per day for three consecutive days, followed by a drug holiday period of 2 days.

(193) F13. The method of any one of claims F10-F12, wherein step (ii) comprises administering to the subject cytarabine at a dose of about 1 g/m.sup.2 to about 3 g/m.sup.2 by intravenous injection in about 72 hours.

(194) F14. The method of any one of claims F1-F13, wherein the subject is MCL-1 dependent.

(195) F15. The method of any one of claims F1-F14, wherein the subject is identified as MCL-1 dependent.

(196) F16. The method of claim F15, wherein the subject is identified as MCL-1 dependent by examining a bone marrow sample of the subject.

(197) F17. The method of any one of claims F1-F16, wherein the subject is measurable residual disease (MRD)-positive prior to being administered the first and second courses of treatment.

(198) F18. The method of any one of claims F1-F17, wherein the subject is measurable residual disease (MRD)-negative after being administered the first and second courses of treatment.

(199) F19. The method of any one of claims F1-F18, further comprising detecting the measurable residual disease (MRD) status of the subject.

(200) F20. The method of claim F19, wherein the MRD status of the subject is detected prior to administering the first and second courses of treatment to the subject.

(201) F21. The method of claim F19, wherein the MRD status of the subject is detected after administering the first and second courses of treatment to the subject.

(202) F22. The method of any one of claims F18-F20, wherein the MRD status of the subject is detected prior to and after administering the first and second courses of treatment to the subject.

(203) F23. The method of any one of claims F1-F22, further comprising terminating administration of at least the first course of treatment to the subject if the subject is determined to be measurable residual disease (MRD)-negative.

Example 1. Alvocidib Monotherapy

(204) Provided herein is a prophetic example describing an exemplary alvocidib monotherapy regimen for treating AML with venetoclax failure.

(205) Human patients having primary refractory AML after up to 2 cycles of venetoclax treatment or having relapsed AML with a First Complete Remission (CR1) period of >90 days to ≤18 months after venetoclax treatment can be subject to this monotherapy.

(206) The monotherapy includes 4-8 treatment cycles, each of which includes 28 days (4 weeks). In each treatment cycle, alvocidib is given to the AML patient at a dose of 25 mg/m.sup.2 via an intravenous bolus of 30 minutes on Day 1 of Week 1. In Weeks 2 and 3 (e.g., on Day 1 of Week 2 and Day 1 of Week 3), alvocidib is given to the AML patient at a dose of 50 mg/m.sup.2 via an intravenous bolus for 30 minutes. The patient then has a 1-week alvocidib-free (drug holiday) period.

Example 2. Alvocidib in Combination with Low Dose Cytarabine

(207) This is a prophetic example describing a Phase 2, open label, clinical study in patients with AML, who have progressed due to resistance or relapse (i.e., after complete remission) following treatment with venetoclax, either alone or in combination with azacitidine or decitabine.

(208) In this study, the human subjects were previously treated with venetoclax, optionally in combination with azacitidine or decitabine, and were considered ineligible for induction therapy, including: a. ≥75 years of age b. ≥18 to 65 years of age with at least one of the following comorbidities that preclude use of intensive induction chemotherapy: i. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; ii. Cardiac history of Congestive Heart Failure (CHF) requiring treatment or Ejection Fraction≤50% or chronic stable angina; iii. Diffusing capacity of the Lung for Carbon Monoxide (DLCO)<=65% or Forced Expiratory Volume in 1 second (FEV1)≤65%; iv. Creatinine clearance≥30 mL/min to <45 ml/min; v. Moderate hepatic impairment with total bilirubin>1.5 to ≤3.0×Upper Limit of Normal (ULN); vi. Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Therapeutic Medical Director during screening and before study enrollment.

(209) Provide written informed consent prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)

(210) To be eligible for participation in the study, patients must meet all of the following inclusion criteria: 1. Be ≥18 years of age 2. Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of >5% blasts based on histology or flow cytometry 3. Have demonstrated progression on prior venetoclax combined with azacitidine or decitabine 4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS)≤2 5. Have a serum creatinine level≤1.8 mg/dL 6. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level≤5 times upper limit of normal (ULN) 7. Have a total bilirubin level≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia) 8. Have a left ventricular ejection fraction (LVEF)>45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan 9. Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate during and for 6 months after completion of study therapy

(211) Patients meeting any one of these exclusion criteria will be prohibited from participating in this study. 1. Received any previous treatment with alvocidib or any other CDK inhibitor 2. Require concomitant chemotherapy, radiation therapy, or immunotherapy Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting treatment on either arm 3. Have a peripheral blast count of >30,000/mm.sup.3 (may use hydroxyurea as in #5 above) 4. Received antileukemic therapy within the last 3 weeks (with the exception of hydroxyurea or if the patient has definite refractory disease). Refractory patients who received therapy within the last 3 weeks may be eligible with prior approval of the Medical Monitor 5. Diagnosed with acute promyelocytic leukemia (APL, M3) 6. Have active central nervous system (CNS) leukemia 7. Have evidence of uncontrolled disseminated intravascular coagulation 8. Have an active, uncontrolled infection 9. Have other life-threatening illness 10. Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia 11. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol 12. Are pregnant and/or nursing 13. Have received any live vaccine within 14 days prior to first study drug administration

(212) The patients are given a combination therapy including 4-8 treatment cycles, each of which contains 28 days. Each treatment cycle consists of (i) alvocidib administered at a dose of 25 mg/m.sup.2 as a 30 minute intravenous (IV) bolus daily on Day 1, followed by a first drug holiday period on Day 2; (ii) cytarabine administered at a dose of 20 mg/m.sup.2 by subcutaneous injection on Days 3 through 12 (10 days) followed by 2 days of rest (a drug holiday period), and (iii) alvocidib administered at a dose of 50 mg/m.sup.2 as a 30 minute intravenous (IV) bolus on Day 15, followed by 13 days of rest (on Days 16-28).

(213) Supportive care is provided and includes the following: tumor lysis prevention and treatment (e.g., mandatory hydration with saline or similar hydration fluid); diligent monitoring of urine output; mandatory allopurinol orally each day of dosing during treatment cycle 1 (optional in subsequent cycles); mandatory oral phosphate binder to be started at the same time as initiation of IV hydration during cycle 1 (optional in subsequent cycles), unless contraindicated; evaluation of laboratory indicators of tumor lysis syndrome (TLS) during treatment cycle 1; monitoring fibrinogen levels at baseline and then as clinically indicated; and prophylactic antibiotic, antiviral, and/or antifungal therapy.

(214) The efficacy assessments performed in the study include response assessments as defined by the International Working Group Criteria and 2017 European LeukemiaNet, safety assessments, treatment assessments, and pharmacodynamic assessments. The response assessments included complete remission rate, overall survival, combined complete remission rate (e.g., complete remission plus complete hematologic remission), combined response rate (e.g., complete remission plus complete hematologic remission plus partial remission), and event-free survival. Treatment assessments included bone marrow biopsies and/or aspirates performed before treatment and at hematologic recovery (i.e., absolute neutrophil count (ANC)>1000 μL and platelet count>100,000 μL) or Day 45, whichever occurred first. In addition, complete blood counts and chemistries are assessed daily during hospitalization for chemotherapy administration and weekly thereafter. Pharmacodynamic assessments include determination of MCL-1 dependence at baseline using bone marrow.

Example 3. Alvocidib in Combination with Hypomethylating Agents (HMA)

(215) Provided herein is a prophetic example describing an exemplary alvocidib therapy in combination with an HMA agent such as decitabine or azacitidine for treating AML with venetoclax failure.

(216) Human patients having primary refractory AML after up to 2 cycles of venetoclax treatment or having relapsed AML with a First Complete Remission (CR1) period of >90 days to ≤18 months after venetoclax treatment can be subject to this therapy.

(217) The therapy described in this Example may contain multiple treatment cycles as needed, for example, 4-8 treatment cycles. Each treatment cycle includes 28 days (4 weeks). In each treatment cycle, decitabine may be given to a subject on a daily basis on Days 1-5 (may extend to up to 10 days in some instances) at a daily dose of from about 15 mg/m.sup.2 to about 45 mg/m.sup.2, preferably, about 20 mg/mgt. After a drug holiday period (e.g., having 1-4 days such as 2 days, e.g., on Day 6 and 7), alvocidib is given to the AML patient at a dose of from about 20 mg/m.sup.2 to about 90 mg/m.sup.2 via an intravenous injection for 1-4 days, for example, on Day 8. Alvocidib may be given to the subject as an intravenous bolus of 30 minutes. Alternatively, a portion of the daily dose may be given to the subject (e.g., between about 10 mg/m.sup.2 and about 30 mg/m.sup.2, such as about 20 mg/m.sup.2) as an intravenous bolus for 30 minutes, and the remaining dose (e.g., between about 10 mg/m.sup.2 to about 60 mg/m.sup.2, such as about 10 mg/m.sup.2, about 20 mg/m.sup.2, about 30 mg/m.sup.2, about 45 mg/m.sup.2, or about 60 mg/m.sup.2) can be given to the subject by intravenous infusion in about 3 to about 6 hours, such as about 4 hours. The subject can then have a drug holiday period of about 15 to about 25 days, for example, about 20 days (e.g., on Days 9-28).

Example 4. Phase 2 Study of Alvocidib in Patients With Relapsed/Refractory Acute Myeloid Leukemia Following Treatment with Venetoclax Combination Therapy

(218) This study will evaluate the safety and efficacy of alvocidib in patients with AML who have either relapsed from (e.g., experience reoccurrence of disease following a CR/CR.sub.i with duration of greater than or equal to 90 days) or are refractory to (e.g., failed to achieve a CR/CR.sub.i, or achieved a CR/CR.sub.i with duration of less than 90 days) induction therapy with venetoclax in combination with azacytidine or decitabine.

(219) The following inclusion criteria apply to this study: 1. Be ≥18 years of age. 2. Have an established, pathologically confirmed diagnosis of AML by World Health Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of >5% blasts based on histology or flow cytometry. 3. Have received initial induction therapy with venetoclax in combination with azacytidine or decitabine and were either refractory (failed to achieve a CR/CRi or achieved a CR/CRi with duration<90 days) or have relapsed (reoccurrence of disease following a CR/CRi with duration≥90 days). 4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS)≤2. 5. Have a glomerular filtration rate (GFR)≥30 mL/min using the Cockcroft-Gault equation. 6. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level≤5 times upper limit of normal (ULN). 7. Have a total bilirubin level≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia). 8. Be infertile or agree to use an adequate method of contraception: sexually active patients and their partners must use an effective method of contraception associated with a low failure rate prior to study entry, for the duration of study participation, and for at least 3 months (males) and 6 months (females) after the last dose of study drug. 9. Be able to comply with the requirements of the entire study. 10. Provide written informed consent prior to any study related procedure: in the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.

(220) The following exclusion criteria apply to this study: 1. Received a previous treatment with alvocidib or another CDK inhibitor, or received prior anti-leukemic therapy other than first-line venteoclax in combination with azacytidine or decitabine. 2. Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting treatment on either arm. 3. Received an allogeneic stem cell transplant within 60 days of the start of study treatment. Patients who received an allogeneic stem cell transplant must be off all immunosuppressants at the time of study treatment. 4. Are receiving or have received systemic therapy for graft-versus-host disease. 5. Have a peripheral blast count of >30,000/mm.sup.3 (may use hydroxyurea as in #2 above). 6. Received antileukemic therapy within the last 3 weeks (with the exception of hydroxyurea or if the patient has definite refractory disease). Refractory patients who received therapy within the last 3 weeks may be eligible with prior approval of the Medical Monitor. 7. Diagnosed with acute promyelocytic leukemia (APL-M3). 8. Have active central nervous system (CNS) leukemia. 9. Have evidence of uncontrolled disseminated intravascular coagulation. 10. Have an active, uncontrolled infection. 11. Have other life-threatening illness. 12. Have other active malignancies requiring treatment or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia. 13. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol. 14. Are pregnant and/or nursing. 15. Have received any live vaccine within 14 days prior to first study drug administration.

(221) This is an open-label, randomized, two-stage clinical study. Stage 1 of the study is randomized, and consists of two arms (26 patients per arm). In Stage 1, 26 patients will be randomized into each of the two treatment arms stratified by prior response to venetoclax in combination with azacytidine or decitabine: refractory or relapsed.

(222) As an additional safety measure, given the unique patient population and outpatient treatment administration, a lead-in cohort of six patients (three patients in each of the Stage 1 treatment arms) will be enrolled, treated and evaluated for dose-limiting toxicities (DLTs). Three patients in each arm of the lead-in cohort may be enrolled and treated simultaneously. In the absence of any dose-limiting toxicity (DLT), the study will proceed as outlined and randomization will begin into Arm 1 or Arm 2. If a patient in the lead-in cohort experiences a DLT during the first cycle, then the alvocidib doses for that patient will be reduced by 25% (to Dose Level −1), as shown in Table 1. That arm of the lead-in cohort will be expanded by at least one patient to determine whether the event was isolated in nature. If no additional DLTs are observed, the study will proceed as outlined. Once all 6 patients have been treated in the lead-in cohort with ≤1 DLT observed, patients will be accrued and randomized into Arm 1 or Arm 2. However, should ≥2 patients in a lead-in arm experience a DLT, a clinical meeting would be scheduled to discuss continuing the study as currently designed.

(223) TABLE-US-00001 TABLE 1 Stage Study Drug Dosing Dose Level Dose 1 Component Days 1 Level -1.sup.a Arm 1 Alvocidib.sup.b 1 25 mg/m.sup.2 19 mg/m.sup.2 IV bolus IV bolus Cytarabine 3 through 20 mg/m.sup.2 20 mg/m.sup.2 12 SC injection SC injection Alvocidib.sup.b 15 50 mg/m.sup.2 39 mg/m.sup.2 IV bolus IV bolus Arm 2 Alvocidib.sup.b 1 25 mg/m.sup.2 19 mg/m.sup.2 IV bolus IV bolus Alvocidib 8, 15 50 mg/m.sup.2 39 mg/m.sup.2 IV bolus IV bolus .sup.aDose Level -1 to be used should a DLT be observed in the lead-in cohort of 6 patients (3 patients/treatment arm) .sup.bAlvocidib to be administered as an IV bolus over 30 to 60 minutes

(224) Those patients in Arm 1 are given alvocidib and low dose cytarabine on a 28-day treatment cycle. On Day 1, patients in Arm 1 are given 25 mg/m.sup.2 alvocidib as a 30-60-minute intravenous (IV) bolus. On Days 3 through 12 (10 days), patients in Arm 1 are given 20 mg/m.sup.2 cytarabine by subcutaneous (SC) injection each day. On Day 15, patients in Arm 1 are given 50 mg/m.sup.2 alvocidib as a 30-60-minute IV bolus. Those patients in Arm 2 of the study are given alvocidib on a 28-day treatment cycle. On Day 1, patients in Arm 2 are given 25 mg/m.sup.2 alvocidib as a 30-60-minute IV bolus. On Days 8 and 15, patients in Arm 2 are given 50 mg/m.sup.2 alvocidib as a 30-60-minute IV bolus.

(225) Stage 2 of the study consists of 76 patients, who will be dosed with a regimen selected based on Stage 1 performance.

(226) Patients who achieve CR, CR.sub.i, CR.sub.h, MLFS or PR after the first cycle (completion of all doses) may receive additional optional cycles of treatment until disease progression. Patients not demonstrating evidence of CR, CR.sub.i, CR.sub.h, MLFS or PR after 4 cycles of treatment will be considered for removal from the study, although with permission of the Medical Monitor, treatment may continue if clinically indicated and provided there is no evidence of toxicity≥NCI CTCAE Grade 4.

(227) Supportive care may be provided, and may include the following: tumor lysis prevention and treatment (e.g., mandatory IV hydration with 0.45% NaCl (or similar hydration fluid per institutional standard) sterile solution at 500 cc for 1-2 hours prior to alvocidib, then an additional 500 cc for 1-2 hours after alvocidib during Cycle 1 (optional for subsequent cycles for patients who have achieved a CR)); replacement of excessive fluid losses, including from diarrhea, should be done unless otherwise clinically indicated (over-the-counter measures are typically effective in this setting if initiated early; persistent diarrhea despite optimal outpatient management would trigger medical consultation); mandatory oral allopurinol to be started at least 72 hours prior to Day 1 of Cycle 1 and continued until completion of the first cycle (i.e., 28 days) (this may be discontinued for subsequent treatment cycles if uric acid levels are within normal limits and there is no evidence of TLS); mandatory oral phosphate binder to be started at the same time as initiation of IV hydration on Day 1 of Cycle 1 and continued for the first week (i.e., 7 days) (this may be discontinued for subsequent treatment cycles if serum phosphorus levels are <3 after the first treatment with alvocidib and there is no evidence of TLS); evaluation of laboratory indicators of TLS during Cycle 1 (obtain a STAT serum potassium at the end of alvocidib infusion; tumor lysis laboratory evaluations (tumor lysis labs) include electrolytes (sodium, potassium, chloride, and carbon dioxide) as well as creatine, calcium, lactate dehydrogenase, uric acid, and phosphorous levels; monitor tumor lysis labs prior to infusion and two hours (±30 minutes) after completion of IV hydration post-alvocidib (labs will also be drawn daily for the first three days following the first alvocidib dose (Days 2-4, and at least weekly for the remainder of Cycle 1); during Cycles 2+, tumor lysis labs will be assessed prior to each dose of alvocidib; and monitor fibrinogen levels at baseline and then as clinically indicated); infection prevention (prophylactic antibiotics including levofloxacin (or equivalent) 500 mg orally once daily and azole antifungals (e.g., fluconazole, posaconazole, voriconazole, isavuconazole) should be administered to patients in all treatment arms if ANC<500/μL, and can be discontinued when the ANC≥500/μL per institutional standards and physician's discretion, valacyclovir (or equivalent) to be administered daily to all patients throughout the study based on institutional standards unless there are contraindications); routine growth factor support is not allowed; growth factor support can be given at the discretion of the Investigator and with the Medical Monitor's approval in the presence of life threatening infection with ongoing neutropenia; donor lymphocyte infusions are not allowed at any time during the study).

(228) The efficacy assessments performed in the study include response assessments as defined by the International Working Group Criteria and 2017 European LeukemiaNet, safety assessments, treatment assessments, and pharmacodynamic assessments. The response assessments include complete remission rate; CR.sub.MRD−, defined as patients achieving CR whose bone marrow is determined to be negative for MRD using standardized techniques (e.g., multiparametric flow cytometry, molecular testing including next generation sequencing); median overall survival (time from treatment (Day 1) until death from any cause); CR rate, defined as the percentage of patients achieving CR (defined as bone marrow blasts<5%, absence of blasts with Auer rods, absence of extramedullary disease, and hematologic recovery (absolute neutrophil count (ANC)≥1,000/μL and platelet count≥100,000/μL)); composite CR rate, defined as the percentage of patients achieving CR, CR, (defined as meeting all CR criteria but with only full recovery of one peripheral blood cell type (ANC≥1,000/μL or platelet count≥100,000/μL)) or CR.sub.h (defined as CR with only partial recovery of both peripheral blood cell types (ANC≥500/μL and platelet count≥50,000/μL); combined response rate, defined as the combined percentage of patients achieving at least one of the following: CR, CR.sub.i, CR.sub.h, morphologic leukemia free state (MLFS; bone marrow blasts of less than 5%, absence of blasts with Auer rods, absence of extramedullary disease, no hematologic recovery required) and partial remission (PR; meets all hematologic values required for CR, but with a decrease of at least 50% in the percentage of blasts to greater than or equal to 5% to less than or equal to 25% in bone marrow); event-free survival (EFS; time from first treatment (Day 1) until (a) treatment failure, (b) relapse after CR, CR.sub.i or CR.sub.h, or (c) death from any cause, whichever occurs first, censored at 2 years); duration of composite CR, defined as time from first documented response of CR, CR.sub.i or CR.sub.h to relapse or death from any cause; rates of 28- and 56-day transfusion independence (TI; defined as percentages of patients who do not receive red blood cell (RBC) transfusions, platelet (PLT) transfusions, or RBC and PLT transfusions for 28 days and 56 days, respectively).

(229) Safety and tolerability of the regimen will be assessed by analyzing the incidence rates of treatment-emergent adverse events (TEAEs) summarized at the MedDRA preferred term and primary system organ class levels. Similar summaries will be made for subsets of adverse events (AEs) such as (1) those judged by the Investigator to be related to study treatment, and (2) serious adverse events (SAEs).

(230) Safety and tolerability of the regimen will be assessed by analyzing the incidence rates of treatment-emergent adverse events (TEAEs) summarized at the MedDRA preferred term and primary system organ class levels. Similar summaries will be made for subsets of adverse events (AEs) such as (1) those judged by the Investigator to be related to study treatment, and (2) serious adverse events (SAEs).

(231) Other routine safety assessments (e.g., clinical laboratory parameters and vital signs) will be summarized by shift tables and treatment group using mean, standard deviation, median, minimum and maximum changes from baseline values.

(232) Mortality (all causes) at 30 and 60 days following last treatment will also be calculated.

(233) Adverse events will be graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

(234) A Data Safety Monitoring Board (DSMB) will monitor key outcomes from the study.

Other Embodiments

(235) While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.

(236) The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

(237) The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

(238) As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

(239) As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

(240) In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.