DOSING OF A BRUTON'S TYROSINE KINASE INHIBITOR

Abstract

The present invention provides a method of administering doses of the BTK inhibitor, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof for use in treating conditions such as cancer and autoimmune diseases.

Claims

1-26. (canceled)

27. A method of treating a BTK-mediated cancer in a patient, comprising administering to the patient in need thereof a dose between about 120 mg and about 600 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein the dose is about 200 mg.

29. The method of claim 27, wherein the dose is administered once daily.

30. The method of claim 27, wherein the dose is administered orally.

31. The method of claim 30, wherein the dose is administered as one or more tablets.

32. The method of claim 30, wherein the dose is administered as one or more capsules.

33. The method of claim 31, wherein each tablet comprises about 25 mg, about 50 mg, or about 100 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

34. The method of claim 32, wherein each capsule comprises about 25 mg, about 50 mg, or about 100 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

35. The method of claim 27, wherein the BTK-mediated cancer is selected from one or more of B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, ABC-DLBCL, follicular lymphoma, hairy cell leukemia, and B-cell non-Hodgkin lymphoma.

36. The method of claim 35, wherein the BTK-mediated cancer is mantle cell lymphoma.

37. The method of claim 35, wherein the BTK-mediated cancer is chronic lymphocytic leukemia or small lymphocytic lymphoma.

38. A method of treating mantle cell lymphoma in a patient, comprising administering orally to the patient in need thereof a daily dose of about 200 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

39. The method of claim 38, wherein the daily dose of about 200 mg is administered in the form of two 100-mg tablets or capsules.

40. A method of treating chronic lymphocytic leukemia or small lymphocytic lymphoma in a patient, comprising administering orally to the patient in need thereof a daily dose of about 200 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

41. The method of claim 40, wherein the daily dose of about 200 mg is administered in the form of two 100-mg tablets or capsules.

42. The method of claim 27, wherein the dose is a first daily dose of about 200 mg.

43. The method of claim 16, comprising: (a) monitoring the patient for one or more symptoms selected from toxicity, a clinically significant adverse event, intolerability, and a drug-drug interaction; and (b) administering a second daily dose of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof if the patient exhibits the one or more symptoms, wherein the second daily dose is reduced as compared to the first daily dose.

44. The method of claim 43, wherein the second daily dose is reduced by 100 mg as compared to the first daily dose.

45. A method of treating a BTK-mediated cancer in a patient suffering from one or more clinically significant adverse events, comprising: (a) administering to the patient a daily dose of about 200 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, (b) monitoring the patient for one or more clinically significant adverse events; and (c) administering a reduced daily dose of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof if the patient exhibits one or more clinically significant adverse events.

46. The method of claim 45, wherein the one or more clinically significant adverse events is one or more of non-hematological toxicity, neutropenia, and thrombocytopenia.

47. The method of claim 46, wherein the one or more of non-hematological toxicity, neutropenia, and thrombocytopenia are Grade 3 or greater.

48. The method of claim 47, wherein the thrombocytopenia is Grade 4.

49. The method of claim 47, wherein the thrombocytopenia is with bleeding.

50. The method of claim 47, wherein the neutropenia is with one or more of fever and infection.

51. The method of claim 47, wherein the neutropenia is Grade 4.

52. The method of claim 45, wherein the reduced daily dose is about 100 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

53. The method of claim 45, wherein the reduced daily dose is about 50 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

54. The method of claim 45, wherein the one or more clinically significant adverse events is atrial fibrillation.

55. The method of claim 45, wherein the one or more clinically significant adverse events is hemorrhage.

56. The method of claim 45, wherein (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof is not administered to the patient for between 1 and up to 28 days before administering the reduced daily dose.

57. A method of treating a BTK-mediated cancer in a patient suffering from one or more clinically significant adverse events, comprising: (a) administering to the patient a daily dose of about 200 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (b) monitoring the patient for one or more clinically significant adverse events; (c) withdrawing the administration of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide if the patient exhibits one or more clinically significant adverse events until recovery or baseline; and (d) administering a daily dose of about 100 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, wherein one or more clinically significant adverse events is one or more of non-hematological toxicity, neutropenia, and thrombocytopenia.

58. The method of claim 57, wherein the one or more of non-hematological toxicity, neutropenia, and thrombocytopenia is Grade 3 or greater.

59. The method of claim 58, wherein the non-hematological toxicity is Grade 3.

60. The method of claim 58, wherein the neutropenia is Grade 3 with one or more of fever and infection.

61. The method of claim 58, wherein the thrombocytopenia is Grade 3 with bleeding.

62. The method of claim 58, wherein the thrombocytopenia is Grade 4.

63. A method of treating a BTK-mediated cancer in a patient suffering from one or more clinically significant adverse events, comprising: (a) administering to the patient a daily dose of about 200 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (b) monitoring the patient for one or more clinically significant adverse events; (c) withdrawing the administration of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide if the patient exhibits one or more clinically significant adverse events until recovery or baseline; and (d) administering a daily dose of about 50 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, wherein the one or more clinically significant adverse events is non-hematological toxicity, neutropenia, and/or thrombocytopenia.

64. The method of claim 63, wherein the one or more of non-hematological toxicity, neutropenia, and thrombocytopenia is Grade 3 or greater.

65. The method of claim 64, wherein the non-hematological toxicity is Grade 3.

66. The method of claim 64, wherein the neutropenia is Grade 3 with one or more of fever and infection.

67. The method of claim 64, wherein the thrombocytopenia is Grade 3 with bleeding.

68. The method of claim 64, wherein the thrombocytopenia is Grade 4.

69. The method of claim 27, wherein the patient has received one or more prior anti-cancer therapies.

70. The method of claim 69, wherein the patient failed to respond to standard of care of the cancer.

71. The method of claim 69, wherein the patient relapsed after being previously treated with standard of care of the cancer.

72. The method of claim 69, wherein the patient is intolerant to standard of care of the cancer.

73. The method of claim 69, wherein the patient has previously received one or more BTK inhibitors.

74. The method of claim 73, wherein the one or more BTK inhibitors includes one or more covalent BTK inhibitors.

75. The method of claim 73, wherein the patient has failed to respond to the previously-administered one or more BTK inhibitors.

76. The method of claim 75, wherein the one or more BTK inhibitors includes one or more covalent BTK inhibitors.

77. The method of claim 76, wherein the one or more covalent BTK inhibitors is selected from ibrutinib, acalabrutinib, zanubrutinib, and tirabrutinib.

78. The method of claim 69, wherein the patient has previously received one or more anti-cancer therapies selected from a BTK inhibitor and a BCL-2 inhibitor.

79. The method of claim 78, wherein the BTK inhibitor is a covalent BTK inhibitor.

80. The method of claim 78, wherein the BCL-2 inhibitor is venetoclax.

81. A method of treating mantle cell lymphoma in a patient, comprising administering orally to the patient in need thereof a daily dose of about 200 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof and wherein the patient has previously received a BTK inhibitor.

82. The method of claim 81, wherein the BTK inhibitor is a covalent BTK inhibitor.

83. A method of treating chronic lymphocytic leukemia or small lymphocytic lymphoma in a patient, comprising administering orally to the patient in need thereof a daily dose of about 200 mg of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof wherein the patient has previously received a BTK inhibitor and a BCL-2 inhibitor.

84. The method of claim 83, wherein the BTK inhibitor is a covalent BTK inhibitor.

85. A method of treating mantle cell lymphoma in a patient, comprising administering orally to the patient in need thereof about 200 mg once daily of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, wherein the patient has received and failed to respond to one or more anti-cancer therapies.

86. A method of treating chronic lymphocytic leukemia or small lymphocytic lymphoma in a patient, comprising administering orally to the patient in need thereof about 200 mg once daily of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, wherein the patient has received and failed to respond to one or more anti-cancer therapies.

87. The method of claim 27, wherein the dose is administered once daily for one or more 28-day cycles.

88. The method of claim 87, wherein the patient is also administered an anti-CD20 based therapy.

89. The method of claim 88, wherein the anti-CD20 based therapy is rituximab.

90. The method of claim 89, wherein rituximab is administered at about 375 mg/m.sup.2 on Day 1 of a first 28-day cycle.

91. The method of claim 89, wherein rituximab is administered at about 500 mg/m.sup.2 on Day 1 of each of second, third, fourth, fifth, and sixth 28-day cycles.

92. The method of claim 87, wherein the patient is also administered a BCL-2 inhibitor.

93. The method of claim 92, wherein the BCL-2 inhibitor is venetoclax.

94. The method of claim 93, wherein venetoclax is administered during a fourth 28-day cycle at a dose of about 20 mg daily for Days 1-7, about 50 mg daily for Days 8-14, about 100 mg daily for Days 15-21, and about 200 mg daily for Days 22-28 of the cycle.

95. The method of claim 94, wherein venetoclax is administered at about 400 mg daily for each of fifth and six 28-day cycles.

96. The method of claim 92, wherein the BCL-2 inhibitor is N-[[(3S)-3-benzyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazin-7-yl]sulfonyl]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide or a pharmaceutically acceptable salt thereof.

97. The method of claim 96, wherein the BCL-2 inhibitor is N-[[(3S)-3-benzyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazin-7-yl]sulfonyl]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.

98. The method of claim 88, wherein the patient is also administered a BCL-2 inhibitor.

99. The method of claim 98, wherein the anti-CD20 based therapy is rituximab and the BCL-2 inhibitor is venetoclax.

100. The method of claim 98, wherein the anti-CD20 based therapy is rituximab and the BCL-2 inhibitor is N-[[(3S)-3-benzyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazin-7-yl]sulfonyl]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide or a pharmaceutically acceptable salt thereof.

101. The method of claim 100, wherein the BCL-2 inhibitor is N-[[(3S)-3-benzyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazin-7-yl]sulfonyl]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.

102. A method of treating mantle cell lymphoma in a patient that has received one or more anti-cancer therapies, comprising: discontinuing a first covalent BTK inhibitor that causes a hematologic effect; administering a daily dose of about 200 mg of a second BTK inhibitor that does not induce the severity of adverse effects of the first covalent BTK inhibitor, wherein the first covalent BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or tirabrutinib, and the second BTK inhibitor is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, wherein the severity of the hematologic effect is reduced.

103. The method of claim 102, wherein the dose of about 200 mg is administered in the form of two 100-mg tablets or capsules.

104. The method of claim 103, wherein the hematologic effect is atrial fibrillation.

105. The method of claim 103, wherein the hematologic effect is hemorrhage.

106. The method of claim 103, wherein the second BTK inhibitor is administered once daily until disease progression.

107. A method of treating chronic lymphocytic leukemia or small lymphocytic lymphoma in a patient that has received one or more anti-cancer therapies, comprising: discontinuing a first covalent BTK inhibitor that causes a hematologic effect; administering a daily dose of about 200 mg of a second BTK inhibitor that does not induce the severity of adverse effects of the first covalent BTK inhibitor, wherein the first covalent BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or tirabrutinib, and the second BTK inhibitor is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, wherein the severity of the hematologic effect is reduced.

108. The method of claim 107, wherein the dose of about 200 mg is administered in the form of two 100-mg tablets or capsules.

109. The method of claim 108, wherein the hematologic effect is atrial fibrillation.

110. The method of claim 108, wherein the hematologic effect is hemorrhage.

111. The method of claim 108, wherein the second BTK inhibitor is administered once daily until disease progression.

112. The method of claim 27, wherein the dose is administered orally once daily, and wherein the administration of the dose results in an exposure of greater than or equal to about 806 ng/mL within 24 hours of administration.

113. The method of claim 112, wherein the patient has C481S mutated BTK.

114. The method of claim 1, wherein the dose achieves a trough drug concentration at a steady state that inhibits at least 90% of the activity of the wild-type BTK.

115. The method of claim 114, wherein the dose achieves a trough drug concentration at a steady state that inhibits at least 90% of the activity of the C481-mutated BTK.

116. The method of claim 27, wherein the dose is administered orally once daily, and wherein the dose upon administration achieves a steady state AUC.sub.(0-24) of greater than or equal to about 52400 ng*h/mL.

117. The method of claim 116, wherein the AUC.sub.(0-24) is greater than or equal to about 91000 ng*h/mL.

118. The method of claim 27, wherein the dose is administered orally once daily, and wherein the dose upon administration achieves a Cmax of greater than or equal to about 3910 ng/mL.

119. The method of claim 118, wherein the Cmax is greater than or equal to about 5770 ng/mL.

120. The method of claim 27, wherein the BTK-mediated cancer is treated.

121. The method of claim 27, wherein the progression of the BTK-mediated cancer has been restrained, slowed, stopped, or reversed.

122. The method of claim 27, wherein after administration of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof the patient achieves a partial response.

123. The method of claim 27, wherein after administration of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof the patient achieves a complete response.

124. The method of claim 27, wherein after administration of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof the patient achieves a stable disease.

Description

ADDITIONAL EMBODIMENTS

[0695] Embodiment 1. A method of treating cancer or an autoimmune disease in a patient in need thereof comprising administering to the patient a daily dose of between about 120 mg and about 600 mg of a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.
Embodiment 2. The method according to embodiment 1 wherein the method is treating cancer.
Embodiment 3. The method according to either embodiment 1 or 2 wherein the dose is between about 125 mg and about 600 mg.
Embodiment 4. A method of inhibiting proliferation and/or survival of activated B-cells in a patient suffering from a BTK-mediated cancer, comprising: orally administering to the patient suffering from the BTK-mediated cancer a therapeutically effective amount of a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, on a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs,

[0696] wherein the therapeutically effective amount of the compound or salt thereof is an amount that results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours following administration and wherein proliferation and survival of the activated B-cells are inhibited.

Embodiment 5. A method of inhibiting proliferation and/or survival of activated B-cells in a patient suffering from a BTK-mediated cancer, comprising: orally administering to the patient suffering from the BTK-mediated cancer a therapeutically effective amount of a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, on a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs,

[0697] wherein said administration of the therapeutically effective amount results in an AUC.sub.(0-2) of greater than or equal to about 52400 ng*h/mL; and

[0698] wherein said administration of the therapeutically effective amount results in an exposure of greater than or equal to about 806 ng/mL twenty-four hours following said administration.

Embodiment 6. The method according to any one of embodiments 1 to 5 wherein the compound is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide.
Embodiment 7. The method according to any one of embodiments 1 to 6 wherein the dose is administered daily for a 28-day cycle.
Embodiment 8. The method according to any one of embodiments 1 to 2 or 4 to 7 wherein a maximum dose administered per day is between about 120 and about 300 mg.
Embodiment 9. The method according to any one of embodiments 1 to 8 wherein the dose is between about 125 mg and about 300 mg.
Embodiment 10. The method according to any one of embodiments 1 to 9 wherein the dose is between about 150 mg and about 300 mg.
Embodiment 11. The method according to any one of embodiments 1 to 10 wherein the dose is between about 175 mg and about 300 mg.
Embodiment 12. The method according to any one of embodiments 1 to 11 wherein the dose is between about 200 mg and about 300 mg.
Embodiment 13. The method according to any one of embodiments 1 to 10 wherein the dose is about 150 mg.
Embodiment 14. The method according to any one of embodiments 1 to 12 wherein the dose is about 200 mg.
Embodiment 15. The method according to any one of embodiments 1 to 12 wherein the dose is about 300 mg.
Embodiment 16. The method according to embodiment 14 wherein the dose is reduced to 100 mg.
Embodiment 17. The method according to either embodiment 14 or 16 wherein the dose is reduced to 50 mg.
Embodiment 18. The method according to any one of embodiments 1 to 17 wherein the cancer is B-cell non-Hodgkin lymphoma.
Embodiment 19. The method according to embodiment 18 wherein the B-cell non-Hodgkin lymphoma is low-grade B-cell non-Hodgkin lymphoma with transformation.
Embodiment 20. The method according to embodiment 18 wherein the B-cell non-Hodgkin lymphoma is B-cell non-Hodgkin lymphoma with CNS involvement or is a primary CNS lymphoma.
Embodiment 21. The method according to any one of embodiments 1 to 17 wherein the cancer is mantle cell lymphoma.
Embodiment 22. The method according to embodiment 21 wherein the mantle cell lymphoma is blastoid mantle cell lymphoma.
Embodiment 23. The method according to embodiment 21 wherein the mantle cell lymphoma is non-blastoid mantle cell lymphoma.
Embodiment 24. The method according to embodiment 21 wherein the mantle cell lymphoma is with an overexpression of cyclin D1 and/or t(11;14).
Embodiment 25. The method according to any one of embodiments 1 to 17 wherein the cancer is chronic lymphocytic leukemia/small lymphocytic lymphoma.
Embodiment 26. The method according to either embodiment 21 or 25 wherein the patient has Richter's transformation.
Embodiment 27. The method according to either embodiment 21 or 25 wherein the patient has a 17p deletion.
Embodiment 28. The method according to any one of embodiments 21, 25, or 27 wherein the patient has a TP53 mutation.
Embodiment 29. The method according to embodiment 25 wherein the patient has an 11q deletion.
Embodiment 30. The method according to embodiment 25 wherein the patient has unmutated IGHV.
Embodiment 31. The method according to any one of embodiments 1 to 17 wherein the cancer is diffuse large B-cell lymphoma.
Embodiment 32. The method according to embodiment 31 wherein the diffuse large B-cell lymphoma is double hit.
Embodiment 33. The method according to embodiment 31 wherein the diffuse large B-cell lymphoma is double expressor.
Embodiment 34. The method according to any one of embodiments 1 to 17 wherein the cancer is marginal zone lymphoma.
Embodiment 35. The method according to any one of embodiments 1 to 17 wherein the cancer is Waldenstrom's macroglobulinemia.
Embodiment 36. The method according to embodiment 35 wherein the patient has a MYD88 mutation.
Embodiment 37. The method according to embodiment 35 wherein the patient has a CXCR4 mutation.
Embodiment 38. The method according to any one of embodiments 1 to 17 wherein the cancer is multiple myeloma.
Embodiment 39. The method according to any one of embodiments 1 to 17 wherein the cancer is follicular lymphoma.
Embodiment 40. The method according to any one of embodiments 1 to 17 wherein the cancer is B-cell prolymphocytic leukemia.
Embodiment 41. The method according to any one of embodiments 1 to 17 wherein the cancer is hairy cell leukemia.
Embodiment 42. The method according to any one of embodiments 1 to 41 wherein the patient is relapsed or refractory.
Embodiment 43. The method according to any one of embodiments 1 to 41 wherein the patient is treatment naive.
Embodiment 44. The method according to any one of embodiments 1 to 42 wherein the patient received at least one prior anti-cancer therapy.
Embodiment 45. The method according to embodiment 44 wherein the patient received at least one prior anti-cancer therapy that includes at least one BTK inhibitor based therapy.
Embodiment 46. The method according to any one of embodiments 1 to 42 or 44 wherein the patient received no prior anti-cancer therapy containing a BTK inhibitor.
Embodiment 47. The method according to any one of embodiments 1 to 42 or 44 to 46 wherein the patient received one prior anti-cancer therapy.
Embodiment 48. The method according to any one of embodiments 1 to 42 or 44 to 46 wherein the patient received two prior anti-cancer therapies.
Embodiment 49. The method according to any one of embodiments 1 to 42 or 44 to 46 wherein the patient received more than two prior anti-cancer therapies.
Embodiment 50. The method according to any one of embodiments 1 to 49 which further comprises the simultaneous, separate, or sequential administration with a BCL-2 inhibitor and/or an anti-CD20 based therapy.
Embodiment 51. The method according to embodiment 50 wherein the BCL-2 inhibitor is venetoclax.
Embodiment 52. The method according to embodiment 50 wherein the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof.
Embodiment 53. The method according to any one of embodiments 50 to 52 wherein the anti-CD20 based therapy is rituximab.
Embodiment 54. The method according to any one of embodiments 50 to 52 wherein the anti-CD20 based therapy is R-CHOP Embodiment 55. The method according to any one of embodiments 50 to 52 wherein the anti-CD20 based therapy is obinutuzumab.
Embodiment 56. A compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof for use in the treatment of cancer or an autoimmune disease wherein the compound or salt is administered at a daily dose of between about 120 mg and about 600 mg.
Embodiment 57. The compound or salt for use according to embodiment 56 wherein the use is in the treatment is cancer.
Embodiment 58. The compound or salt for use according to either embodiment 56 or 57 wherein the dose is between about 125 mg and about 600 mg.
Embodiment 59. A compound which (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof for use in inhibiting proliferation and/or survival of activated B-cells in a patient suffering from a BTK-mediated cancer, wherein the compound or salt is orally administered to the patient suffering from the BTK-mediated cancer a therapeutically effective amount of the compound or salt, on a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs,

[0699] wherein the therapeutically effective amount of the compound or salt is an amount that results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours following administration and wherein proliferation and survival of the activated B-cells are inhibited.

Embodiment 60. A compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof for use in inhibiting proliferation and/or survival of activated B-cells in a patient suffering from a BTK-mediated cancer, comprising: orally administering to the patient suffering from the BTK-mediated cancer a therapeutically effective amount of the compound or salt thereof, on a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs,

[0700] wherein said administration of the therapeutically effective amount results in an AUC.sub.(0-2) of greater than or equal to about 52400 ng*h/mL; and

[0701] wherein said administration of the therapeutically effective amount results in an exposure of greater than or equal to about 806 ng/mL twenty-four hours following said administration.

Embodiment 61. The compound or salt for use according to any one of embodiments 56 to 60 which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide.
Embodiment 62. The compound or salt for use according to any one of embodiments 56 to 61 wherein the dose is administered daily for a 28-day cycle.
Embodiment 63. The compound or salt for use according to any one of embodiments 56 to 57 and embodiments 59 to 62 wherein a maximum dose administered per day is between about 120 mg and about 300 mg.
Embodiment 64. The compound or salt for use according to any one of embodiments 56 to 63 wherein the dose is between about 125 mg and about 300 mg.
Embodiment 65. The compound or salt for use according to any one of embodiments 56 to 64 wherein the dose is between about 150 mg and about 300 mg.
Embodiment 66. The compound or salt for use according to any one of embodiments 56 to 65 wherein the dose is between about 175 mg and about 300 mg.
Embodiment 67. The compound or salt for use according to any one of embodiments 56 to 66 wherein the dose is between about 200 mg and about 300 mg.
Embodiment 68. The e compound or salt for use according to any one of embodiments 56 to 65 wherein the dose is about 150 mg.
Embodiment 69. The compound or salt for use according to any one of embodiments 56 to 67 wherein the dose is about 200 mg.
Embodiment 70. The compound or salt for use according to any one of embodiments 56 to 67 wherein the dose is about 300 mg.
Embodiment 71. The compound or salt for use according to embodiment 69 wherein the dose is reduced to 100 mg.
Embodiment 72. The compound or salt for use according to either embodiment 69 or 71 wherein the dose is reduced to 50 mg.
Embodiment 73. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is B-cell non-Hodgkin lymphoma.
Embodiment 74. The compound or salt for use according to embodiment 73 wherein the B-cell non-Hodgkin lymphoma is low-grade B-cell non-Hodgkin lymphoma with transformation.
Embodiment 75. The compound or salt for use according to embodiment 73 wherein the B-cell non-Hodgkin lymphoma is B-cell non-Hodgkin lymphoma with CNS involvement or is a primary CNS lymphoma.
Embodiment 76. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is mantle cell lymphoma.
Embodiment 77. The compound or salt for use according to embodiment 76 wherein the mantle cell lymphoma is blastoid mantle cell lymphoma.
Embodiment 78. The compound or salt for use according to embodiment 76 wherein the mantle cell lymphoma is non-blastoid mantle cell lymphoma.
Embodiment 79. The compound or salt for use according to embodiment 76 wherein the mantle cell is with overexpression of cyclin D1 and/or t(11;14).
Embodiment 80. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is chronic lymphocytic leukemia/small lymphocytic lymphoma.
Embodiment 81. The compound or salt for use according to either embodiment 76 or 80 wherein the compound or salt is administered to a patient that has Richter's transformation.
Embodiment 82. The compound or salt for use according to either embodiment 76 or 80 wherein the compound or salt is administered to a patient that has a 17p deletion.
Embodiment 83. The compound or salt for use according to any one of embodiments 76, 80 or 82 wherein the compound or salt is administered to a patient that has a TP53 mutation.
Embodiment 84. The compound or salt for use according to embodiment 80 wherein the compound or salt is administered to a patient that has an 11q deletion.
Embodiment 85. The compound or salt for use according to embodiment 80 wherein the compound or salt is administered to a patient that has unmutated IGHV.
Embodiment 86. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is diffuse large B-cell lymphoma.
Embodiment 87. The compound or salt for use according to embodiment 86 wherein the diffuse large B-cell lymphoma is double hit.
Embodiment 88. The compound or salt for use according to embodiment 86 wherein the diffuse large B-cell lymphoma is double expressor.
Embodiment 89. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is marginal zone lymphoma.
Embodiment 90. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is Waldenstrom's macroglobulinemia.
Embodiment 91. The compound or salt for use according to embodiment 90 wherein the compound or salt is administered to a patient having a MYD88 mutation.
Embodiment 92. The compound or salt for use according to embodiment 90 wherein the compound or salt is administered to a patient having a CXCR4 mutation.
Embodiment 93. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is multiple myeloma.
Embodiment 94. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is follicular lymphoma.
Embodiment 95. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is B-cell prolymphocytic leukemia.
Embodiment 96. The compound or salt for use according to any one of embodiments 56 to 72 wherein the cancer is hairy cell leukemia.
Embodiment 97. The compound or salt for use according to any one of embodiments 56 to 96 wherein the compound or salt is administered to a patient who is relapsed or refractory.
Embodiment 98. The compound or salt for use according to any one of embodiments 56 to 96 wherein the compound or salt is administered to a patient who is treatment naive. Embodiment 99. The compound or salt for use according to any one of embodiments 56 to 97 wherein the compound or salt is administered to a patient who received at least one prior anti-cancer therapy.
Embodiment 100. The compound or salt for use according to embodiment 99 wherein the compound or salt is administered to a patient who received at least one prior anti-cancer therapy that includes at least one BTK inhibitor based therapy.
Embodiment 101. The compound or salt for use according to any one of embodiments 56 to 97 or 99 wherein the compound or salt is administered to a patient who received no prior anti-cancer therapy containing a BTK inhibitor.
Embodiment 102. The compound or salt for use according to any one of embodiments 56 to 97 or 99 to 101 wherein the compound or salt is administered to a patient who received one prior anti-cancer therapy.
Embodiment 103. The compound or salt for use according to any one of embodiments 56 to 97 or 99 to 101 wherein the compound or salt is administered to a patient who received two prior anti-cancer therapies.
Embodiment 104. The compound or salt for use according to any one of embodiments 56 to 97 or 99 to 101 wherein the compound or salt is administered to a patient who received more than two prior anti-cancer therapies.
Embodiment 105. The compound or salt for use according to any one of embodiments 56 to 104 wherein the compound or salt is administered in simultaneous, separate, or sequential administration with a BCL-2 inhibitor and/or an anti-CD20 based therapy.
Embodiment 106. The compound or salt for use according to embodiment 105 wherein the BCL-2 inhibitor is venetoclax.
Embodiment 107. The compound or salt for use according to embodiment 105 wherein the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof.
Embodiment 108. The compound or salt for use according to any one of embodiments 105 to 107 wherein the anti-CD20 based therapy is rituximab.
Embodiment 109. The compound or salt for use according to any one of embodiments 105 to 107 wherein the anti-CD20 based therapy is R-CHOP.
Embodiment 110. The compound or salt for use according to any one of embodiments 105 to 107 wherein the anti-CD20 based therapy is obinutuzumab.