Erdafitinib for intravesical administration for use in the treatment of bladder cancer

Abstract

Provided herein are methods of treatment, erdafitinib for use and use of erdafitinib for the treatment of bladder cancer harboring one or more FGFR alterations comprising locally delivering erdafitinib into the bladder of a patient.

Description

This article provides treatment options, the use of erdatinib, and its application in the treatment of bladder cancer with one or more FGFR alterations, including local delivery of erdatinib into the patient's bladder. Abstract

Claims

Attorney Docket No.: 76166-20023.40CLAIMS We claim:

1. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4- yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L- lactate salt of erdafitinib, is locally delivered in the form of an intravesical drug delivery system comprising: an elongated body configured for intravesical insertion into a patient; and a drug formulation disposed in the elongated body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L- lactate salt of erdafitinib, wherein the drug delivery system is configured to release the erdafitinib from one or more openings in the elongated body, driven by osmotic pressure.

2. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4- yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, to the patient if the one or more FGFR genetic alterations, is present in the sample, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, is locally delivered in the form of an intravesical drug delivery system comprising: an elongated body configured for intravesical insertion into a patient; andAttorney Docket No.: 76166-20023.40a drug formulation disposed in the elongated body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, wherein the drug delivery system is configured to release the erdafitinib from one or more openings in the elongated body, driven by osmotic pressure.

3. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4- yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, is locally delivered in the form of an intravesical drug delivery system comprising: an elongated body configured for intravesical insertion into a patient; and a drug formulation disposed in the elongated body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L- lactate salt of erdafitinib, wherein the drug delivery system is configured to release the erdafitinib from one or more openings in the elongated body, driven by osmotic pressure.

4. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4- yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with aAttorney Docket No.: 76166-20023.40urine based PCR or NGS assay, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, is locally delivered in the form of an intravesical drug delivery system comprising: an elongated body configured for intravesical insertion into a patient; and a drug formulation disposed in the elongated body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L- lactate salt of erdafitinib, wherein the drug delivery system is configured to release the erdafitinib from one or more openings in the elongated body, driven by osmotic pressure.

5. Erdafitinib for use according to any one of the preceding claims, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 or FGFR3 genetic alterations.

6. Erdafitinib for use according to any one of the preceding claims, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 or FGFR3 point mutations or fusions.

7. Erdafitinib for use according to any one of the preceding claims, wherein the one or more FGFR genetic alterations are detected in a urine sample of the patient before locally delivering erdafitinib.

8. Erdafitinib for use according to any one of the preceding claims, wherein erdafitinib is present in the drug delivery system as a mono L-lactate salt.

9. Erdafitinib for use according to any one of the preceding claims, wherein the elongated body comprises a biocompatible elastomer.

10. Erdafitinib for use according to claim 9, wherein the biocompatible elastomer comprises silicone or a thermoplastic polyurethane.

11. Erdafitinib for use according to claim 9, wherein the biocompatible elastomer comprises silicone.Attorney Docket No.: 76166-20023.4012. Erdafitinib for use according to claim 9, wherein the biocompatible elastomer comprises platinum cured silicone elastomer.

13. Erdafitinib for use according to any one of the preceding claims, wherein at least one of the one or more openings in the elongated body is located in a sidewall of the elongated body.

14. Erdafitinib for use according to any one of the preceding claims, wherein at least one of the one or more openings in the elongated body is located at a first end and / or at an opposing second end of the elongated body.

15. Erdafitinib for use according to any one of claims 1 to 12, wherein the drug delivery system has a single opening, which is located in a sidewall of the elongated body at position between a first end and an opposing second end of the elongated body.

16. Erdafitinib for use according to any one of the preceding claims, wherein the one or more openings has a diameter of between about 100 mm and about 200 mm.

17. Erdafitinib for use according to claim 16, wherein the one or more openings has a diameter of about 150 mm.

18. Erdafitinib for use according to any one of the preceding claims, wherein the drug formulation comprises at least one pharmaceutical excipient.

19. Erdafitinib for use according to claim 18, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof.

20. Erdafitinib for use according to claim 18, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.Attorney Docket No.: 76166-20023.4021. Erdafitinib for use according to claim 20, wherein the binder comprises hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof.

22. Erdafitinib for use according to claim 20 or 21, wherein the binder is present in the drug formulation at a total concentration of between about 1 wt% and about 30 wt%, between about 5 wt% and about 20 wt%, or between about 10 wt% and about 15 wt%.

23. Erdafitinib for use according to any one of claims 20 to 22, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, or a combination thereof.

24. Erdafitinib for use according to any one of claims 20 to 23, wherein the diluent (filler) is present in the drug formulation at a total concentration of between about 5 wt% and about 30 wt%, between about 10 wt% and about 30 wt%, or between about 10 wt% and about 20 wt%.

25. Erdafitinib for use according to any one of claims 20 to 24, wherein the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide.

26. Erdafitinib for use according to any one of claims 20 to 25, wherein the glidant is present in the drug formulation at a total concentration of between about 0.05 wt% and about 1 wt%, between about 0.1 wt% and about 0.5 wt%, or about 0.25 wt%.

27. Erdafitinib for use according to any one of claims 20 to 26, wherein the lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol.

28. Erdafitinib for use according to any one of claims 20 to 26, wherein the lubricant comprises magnesium stearate.

29. Erdafitinib for use according to any one of claims 20 to 28, wherein the lubricant is present in the drug formulation at a total concentration of between about 0.05 wt% and about 5 wt%, between about 1 wt% and about 5 wt%, or about 2.5%.Attorney Docket No.: 76166-20023.4030. Erdafitinib for use according to any one of the preceding claims, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular a lactate salt of erdafitinib, and at least one intragranular excipient; and an extragranular composition comprising at least one extragranular excipient.

31. Erdafitinib for use according to claim 30, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient.

32. Erdafitinib for use according to claim 30 or 31, wherein the at least one intragranular excipient comprises an intragranular binder.

33. Erdafitinib for use according to any one of claims 30 to 32, wherein the intragranular binder comprises hydroxypropyl methyl cellulose.

34. Erdafitinib for use according to any one of claims 30 to 33, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, extragranular filler (diluent), extragranular glidant, and extragranular lubricant.

35. Erdafitinib for use according to claim 34, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate.

36. Erdafitinib for use according to any one of claims 34 or 35, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof.

37. Erdafitinib for use according to any one of claims 34 to 36, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide.

38. Erdafitinib for use according to any one of claims 34 to 37, wherein the extragranular lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol.Attorney Docket No.: 76166-20023.4039. Erdafitinib for use according to any one of claims 34 to 38, wherein the extragranular lubricant comprises magnesium stearate.

40. Erdafitinib for use according to any one of the preceding claims, wherein the erdafitinib L-lactate salt is present in the drug formulation in a concentration of from 60 wt% to 91 wt%, or from 60 wt% to 80 wt%.

41. Erdafitinib for use according to claim 40, wherein the erdafitinib L-lactate salt is present in the drug formulation in a concentration of 70 wt%.

42. Erdafitinib for use according to any one of the preceding claims, wherein the drug formulation is in the form of a plurality of mini-tablets.

43. Erdafitinib for use according to claim 42, wherein the drug formulation is in the form of between about 10 and about 100 mini-tablets.

44. Erdafitinib for use according to any one of claims 42 or 43, wherein (a) the formulation comprises a total length of from about 14.5 cm to about 15 cm of mini-tablets, and / or (b) the formulation comprises from about 920 mg to about 965 mg of mini-tablets, or from about 920 mg to about 950 mg of mini-tablets.

45. Erdafitinib for use according to any one of the preceding claims, wherein the drug delivery system is configured to release the erdafitinib by osmotic pressure through the one or more openings in the elongated body.

46. Erdafitinib for use according to any one of the preceding claims, wherein the elongated body comprises an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed.

47. Erdafitinib for use according to claim 46, wherein the annular wall structure has a thickness of between about 0.1 mm to about 0.5 mm.

48. Erdafitinib for use according to claim 47, wherein the annular wall structure has a thickness of about 0.2 mm.Attorney Docket No.: 76166-20023.4049. Erdafitinib for use according to any one of claims 46 to 48, further comprising a first end plug positioned at a first end of the annular wall structure, and a second end plug positioned at a second end of the annular wall structure.

50. Erdafitinib for use according to any one of claims 46 to 49, wherein the one or more openings in the elongated body comprise a single aperture in the annular wall structure, and the elongated body is configured to release the erdafitinib through the aperture.

51. Erdafitinib for use according to any one of claims 46 to 50, wherein the elongated body is configured to release the erdafitinib through microchannels transiently formed at one or both end regions of the annular wall structure.

52. Erdafitinib for use according to any one of the preceding claims, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

53. Erdafitinib for use according to any one of claims 1 to 51, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 6 mg / day.

54. Erdafitinib for use according to any one of claims 1 to 51, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day.

55. Erdafitinib for use according to any one of claims 1 to 51, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

56. Erdafitinib for use according to any one of the preceding claims, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day.

57. Erdafitinib for use according to any one of the preceding claims, wherein the system is configured to release the erdafitinib with a zero order release profile.

58. Erdafitinib for use according to any one of claims 52 to 57, wherein the system is configured to release the erdafitinib for up to about 30 days.Attorney Docket No.: 76166-20023.4059. Erdafitinib for use according to any one of claims 52 to 57, wherein the system is configured to release the erdafitinib for up to about 90 days.

60. Erdafitinib for use according to any one of the preceding claims, wherein the system comprises 500 mg of the erdafitinib (free base equivalent).

61. Erdafitinib for use according to any one of the preceding claims, wherein the system is elastically deformable between a relatively straightened deployment shape suited for insertion through the urethra of a patient and into the patient’s bladder and a retention shape suited to retain the system within the bladder.

62. Erdafitinib for use according to any one of the preceding claims, wherein the system is elastically deformable and comprises a tube having two opposing free ends, which are directed away from one another when the system is in a low-profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape.

63. Erdafitinib for use according to any one of the preceding claims, wherein the system comprises an elastically deformable elongated body having two opposing free ends which lie within the boundaries of a bi-oval-like expanded retention shape.

64. Erdafitinib for use according to any one of the preceding claims, wherein the elongated body further comprises a retention frame lumen.

65. Erdafitinib for use according to claim 64, further comprising a nitinol wire disposed in the retention frame lumen.

66. Erdafitinib for use according to any one of claims 1 to 7, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular an L-lactate salt of erdafitinib, is locally delivered in the form of a pharmaceutical composition comprising erdafitinib L- lactate, and one or more pharmaceutical excipients.

67. Erdafitinib for use according to claim 66, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wettingAttorney Docket No.: 76166-20023.40agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof.

68. Erdafitinib for use according to 66, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.

69. Erdafitinib for use according to claim 68, wherein the binder comprises hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof.

70. Erdafitinib for use according to claim 68 or 69, wherein the binder is present in the drug formulation at a total concentration of between about 1 wt% and about 30 wt%, between about 5 wt% and about 20 wt%, or between about 10 wt% and about 15 wt%.

71. Erdafitinib for use according to any one of claims 68 to 70, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, or a combination thereof.

72. Erdafitinib for use according to any one of claims 68 to 71, wherein the diluent (filler) is present in the drug formulation at a total concentration of between about 5 wt% and about 30 wt%, between about 10 wt% and about 30 wt%, or between about 10 wt% and about 20 wt%.

73. Erdafitinib for use according to any one of claims 68 to 72, wherein the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide.

74. Erdafitinib for use according to any one of claims 68 to 73, wherein the glidant is present in the drug formulation at a total concentration of between about 0.05 wt% and about 1 wt%, between about 0.1 wt% and about 0.5 wt%, or about 0.25 wt%.

75. Erdafitinib for use according to any one of claims 68 to 74, wherein the lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol.Attorney Docket No.: 76166-20023.4076. Erdafitinib for use according to any one of claims 68 to 75, wherein the lubricant comprises magnesium stearate.

77. Erdafitinib for use according to any one of claims 68 to 76, wherein the lubricant is present in the drug formulation at a total concentration of between about 0.05 wt% and about 5 wt%, between about 1 wt% and about 5 wt%, or about 2.5%.

78. Erdafitinib for use according to any one of claims 68 to 77, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular a lactate salt of erdafitinib, and at least one intragranular excipient; and an extragranular composition comprising at least one extragranular excipient.

79. Erdafitinib for use according to claim 78, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient.

80. Erdafitinib for use according to claim 78 or 79, wherein the at least one intragranular excipient comprises an intragranular binder.

81. Erdafitinib for use according to claim 80, wherein the intragranular binder comprises hydroxypropyl methyl cellulose.

82. Erdafitinib for use according to any one of claims 78 to 81, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, extragranular filler (diluent), extragranular glidant, and extragranular lubricant.

83. Erdafitinib for use according to claim 82, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate.

84. Erdafitinib for use according to claim 82 or 83, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof.Attorney Docket No.: 76166-20023.4085. Erdafitinib for use according to any one of claims 82 to 84, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide.

86. Erdafitinib for use according to any one of claims 82 to 85, wherein the extragranular lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol.

87. Erdafitinib for use according to any one of claims 82 to 86, wherein the extragranular lubricant comprises magnesium stearate.

88. Erdafitinib for use according to any one of claims 66 to 87, wherein the erdafitinib L- lactate salt is present in the drug formulation in a concentration of from 60 wt% to 91 wt%, or from 60 wt% to 80 wt%.

89. Erdafitinib for use according to claim 88, wherein the erdafitinib L-lactate salt is present in the drug formulation in a concentration of 70 wt%.

90. Erdafitinib for use according to any one of claims 66 to 89, wherein the composition is in the form of a tablet.

91. Erdafitinib for use according to claim 90, wherein the tablet is a mini-tablet.

92. Erdafitinib for use according to claim 90 or 91, wherein the tablet has a hardness of at least about 100 N.

93. Erdafitinib for use according to claim 92, wherein the tablet has a hardness of between about 150 N and about 250 N.

94. Erdafitinib for use according to claim 92, wherein the tablet has a hardness of between about 175 N and about 225 N.

95. Erdafitinib for use according to any one of claims 90 to 94, wherein the tablet has a thickness of between about 3.2 mm and about 3.6 mm.Attorney Docket No.: 76166-20023.4096. Erdafitinib for use according to claim 91, wherein the mini-tablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side face, circular end faces perpendicular to the cylindrical axis, a diameter across the circular end faces, and a length along the cylindrical side face.

97. Erdafitinib for use according to claim 96, wherein length of the mini-tablet exceeds the diameter of the mini-tablet to provide the mini-tablet with an aspect ratio (length:diameter) of greater than 1:

1.

98. Erdafitinib for use according to claim 96 or 97, wherein the mini-tablet has a diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm.

99. Erdafitinib for use according to claim 96 or 97, wherein the mini-tablet has a diameter of from 2.5 mm to 2.7 mm.

100. Erdafitinib for use according to any one of claims 96 to 99, wherein the mini-tablet has a length of 3.0 mm to 3.5 mm.

101. Erdafitinib for use according to any one of claims 96 to 100, wherein the mini-tablet has a mass of 22 mg to 24 mg.

102. Erdafitinib for use according to any one of claims 51 to 65, wherein the elongated body is configured to release the erdafitinib through the aperture and through microchannels transiently formed at one end region of the annular wall structure.

103. Erdafitinib for use according to any one of claims 50 to 65, wherein the elongated body is configured to release the erdafitinib through the aperture and through microchannels transiently formed at both end regions of the annular wall structure.

104. Erdafitinib for use according to any one of claims 51, 102 or 103, wherein the microchannels transiently form when the osmotic pressure increases above a certain threshold.Attorney Docket No.: 76166-20023.40105. Erdafitinib for use according to any one of the preceding claims, wherein the one or more FGFR genetic alterations is selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3- TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, in particular wherein the FGFR2 genetic alteration and / or the FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) , FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C.

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