Gemcitabine for use in methods of treating high-risk non-muscle invasive bladder cancer unresponsive to bacillus calmette-guerin therapy

Abstract

The present invention provides methods for treatment of high-risk non-muscle invasive bladder cancer that is unresponsive to BCG therapy by locally administering gemcitabine to the bladder. Also provided herein are kits and articles of manufacture for treating high-risk non-muscle invasive bladder cancer that is unresponsive to BCG.

Description

Abstract This invention provides a method for treating high-risk non-muscle-invasive bladder cancer that is unresponsive to BCG treatment, wherein the method involves local application of gemcitabine to the bladder. This invention also provides kits and products for treating high-risk non-muscle-invasive bladder cancer that is unresponsive to BCG.

Claims

What is claimed is:

1. A method of treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in a complete response rate in a population of patients who have received such treatment of at least 50%.

2. A method of bladder sparing in an individual having high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein the individual does not receive a radical cystectomy.

3. A method of treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual who is eligible for radical cystectomy, the method comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks.

4. A method of treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual comprising inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of the individual and removing the intravesical drug delivery system about three weeks later for at least about 24 weeks, wherein such treatment results in a complete response rate in a population of patients who have received such treatment of at least 50%.

5. A method of increasing the complete response rate for treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual comprising administering to the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in a complete response rate that is at least 1.5 fold of the complete response rate achieved by valrubicin in a population of patients who have received such treatment.

6. A method of treating Bacillus Calmette- Guerin (BCG) unresponsive high-risk non-muscle invasive bladder cancer (HR-NMIBC) with carcinoma in situ (CIS) or Tis with or without papillary tumors in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in a complete response rate in a population of patients who have received such treatment of at least 50%.

7. A method of treating Bacillus Calmette- Guerin (BCG) unresponsive high-risk non-muscle invasive bladder cancer (HR-NMIBC) with carcinoma in situ (CIS) with or without papillary tumors in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein the individual has a complete response.

8. A method of inducing a complete response (CR) rate of at least 50% in a patient population with high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette-Guerin (BCG) therapy, the method comprising i) inserting an intravesical drug delivery system comprising about 225 mg gemcitabine into the bladder of an individual with HR-NMIBC, and ii) removing the intravesical drug delivery system about three weeks later, wherein i) and ii) are repeated for at least about 24 weeks.

9. A method of treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in an increased complete response rate compared to the complete response rate achieved by valrubicin.

10. A method of treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual comprising administering about 225 mg of gemcitabine to the bladder of the individual every three weeks (Q3W) for at least about 24 weeks during eight administration periods, wherein each administration period comprises a delivery period of at least seven days when gemcitabine is released from an intravesical drug delivery system, wherein the concentration of gemcitabine in the urine of the individual is at least 4 pg / mL during each delivery period.

11. The method of claim 10, wherein the concentration of gemcitabine in the urine of the individual is between 4 g / mL and 50 pg / mL during each administration period.

12. A method of treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual comprising(a) administering to the bladder of the individual about 225 mg of gemcitabine during an administration period about every three weeks (Q3W) for at least about 24 weeks,(b) inducing a complete response in the individual, and wherein each administration period comprises a delivery period of at least seven days.

13. A method of treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) that is unresponsive to intravesical Bacillus Calmette- Guerin (BCG) therapy in an individual comprisingi) a 24 week induction phase comprising administering about 225 mg gemcitabine to the bladder of the individual about every 3 weeks (Q3W) during an administration period, and ii) an 18 month maintenance phase comprising administering about 225 mg gemcitabine to the bladder of the individual about every twelve weeks during an administration period, wherein each administration period comprises a delivery period of at least seven days when gemcitabine is released from an intravesical drug delivery system, and wherein the intravesical drug delivery system is removed about 3 weeks after each administration.

14. The method of claim 13, wherein after each administration period in i) the intravesical drug delivery system is removed and replaced with a new intravesical drug delivery system for a total of about 24 weeks.

15. The method of any one of claims 1-9, wherein about 225 mg of gemcitabine is administered to the individual during an administration period.

16. The method of any one of claims 10-15, wherein each administration period is about three weeks.

17. The method of any one of claims 10-16, wherein each administration period begins with inserting a drug delivery system comprising about 225 mg gemcitabine into the bladder and each administration period ends with removing the drug delivery system from the bladder.

18. The method of any one of claims 1-9 or 13-16, wherein gemcitabine is released into the bladder during a delivery period.

19. The method of claim 18, wherein the delivery period is less than the administration period.

20. The method of claim 18 or claim 19, wherein the delivery period is about one week to about three weeks.

21. The method of any one of claims 1-20, wherein the gemcitabine administered to the individual is a monotherapy for treatment of the HR-NMIBC that is unresponsive to intravesical BCG therapy.

22. The method of any one of claims 2, 3, 7, 8, or 10-13, wherein such treatment results in a complete response rate in a population of patients who have received such treatment of at least 50%.

23. The method of any one of claims 1, 4-6, 9, or 22, wherein the complete response rate in the population of patients is between about 71% to about 91%.

24. The method of any one of claims 1, 4-6, 9, 22, or 23, wherein the complete response rate in the population of patients is improved compared to the standard of care, optionally wherein the complete response rate in the population of patients is improved at least 1.5 fold compared to the complete response rate for standard of care.

25. The method of any one of claims 1, 4-6, 9, or 22-24, wherein the complete response rate in the population of patients is improved compared to a checkpoint inhibitor therapy, optionally wherein the complete response rate is improved at least 1.5 fold compared to the complete response rate for the checkpoint inhibitor therapy.

26. The method of any one of claims 1, 4-6, 9, or 22-24, wherein the complete response rate in the population of patients is improved compared to treatment with valrubicin, optionally wherein the complete response rate is improved at least 1.5 fold compared to the complete response rate for valrubicin.

27. The method of any one of claims 1-26, wherein the individual has a complete response within three months of the start of treatment with gemcitabine.

28. The method of any one of claims 1, 4-6, 9, or 22-27, wherein a complete response is determined on the basis of a negative cytology analysis and / or on the basis of a negative biopsy.

29. The method of any one of claims 1-28, wherein the individual is administered gemcitabine within 12 months of completion of a last dose of BCG therapy.

30. The method of any one of claims 1-29, wherein the individual has received i) a minimum of five of six full doses of an induction course of BCG; and ii) two or three doses of a maintenance course, or two of six doses of a second induction course of BCG therapy.

31. The method of any one of claims 1-30, wherein the individual has carcinoma in situ (CIS) and / or wherein the population of patients comprises one or more individuals with CIS.

32. The method of any one of claims 1-31, wherein the individual has a histologically confirmed diagnosis of persistent or recurrent CIS and / or wherein the population of patients comprises one or more individuals with a histologically confirmed diagnosis of persistent or recurrent CIS.

33. The method of any one of claims 1-32, wherein the individual has Ta stage bladder cancer, and / or wherein the population of patients comprises one or more individuals with Ta stage bladder cancer; wherein the individual has high grade Ta stage bladder cancer and / or wherein the population of patients comprises one or more individuals with high grade Ta stage bladder cancer; wherein the individual has T1 stage bladder cancer and / or wherein the population of patients comprises one or more individuals with T1 stage bladder cancer; or wherein the individual has high grade T1 stage bladder cancer and / or wherein the population of patients comprises one or more individuals with high grade T1 stage bladder cancer.

34. The method of any one of claims 1-33, wherein the individual has papillary bladder cancer and / or wherein the population of patients comprises one or more individuals with papillary bladder cancer.

35. The method of any one of claims 1-34, wherein the individual is ineligible or elected not to undergo radical cystectomy.

36. The method of claim 35, wherein the individual elected not to undergo radical cystectomy due to bladder preservation or concern about quality of life after bladder removal.

37. The method of any one of claims 1-36, comprising performing a transurethral resection of bladder tumor (TURBT) if the individual has papillary bladder cancer.

38. The method of claim 37, wherein the individual has carcinoma in situ (CIS) followingTURBT.

39. The method of any one of claims 1-38, wherein the individual is renally impaired and / or hepatically impaired.

40. The method of any one of claims 1-39, wherein the individual is at least 65 years old.

41. The method of any one of claims 1-40, wherein treatment with gemcitabine causes tumor ablation.

42. The method of any one of claims 11-41, wherein following treatment with gemcitabine, the individual does not receive a transurethral resection of bladder tumor (TURBT).

43. The method of any one of claims 1-42, wherein the individual does not progress to muscle-invasive bladder cancer.

44. The method of any one of claims 1-43, wherein the quality-of-life score of the individual is maintained or increases following treatment with gemcitabine.

45. The method of any one of claims 1-44, comprising i) inserting an intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder of the individual; ii) removing the intravesical drug delivery system about three weeks later; iii) inserting a new intravesical drug delivery system comprising about 225 mg of gemcitabine into the bladder on the day that the intravesical drug delivery system is removed in step ii), iv) removing the intravesical drug delivery system about three weeks later; wherein steps ii) and iii) are completed seven times.

46. The method of any one of claims 1-45, comprising a dosing schedule of at least 24 weeks comprising i) inserting a first intravesical drug delivery system into the bladder in week 0, and removing the first intravesical drug delivery system in week 3; ii) inserting a second intravesical drug delivery system into the bladder in week 3 after removing the first intravesical drug delivery system, and removing the second intravesical drug delivery system in week 6;iii) inserting a third intravesical drug delivery system into the bladder in week 6 after removing the second intravesical drug delivery system, and removing the third intravesical drug delivery system in week 9; iv) inserting a fourth intravesical drug delivery system into the bladder in week 9 after removing the third intravesical drug delivery system, and removing the fourth intravesical drug delivery system in week 12; v) inserting a fifth intravesical drug delivery system into the bladder in week 12 after removing the fourth intravesical drug delivery system, and removing the fifth intravesical drug delivery system in week 15; vi) inserting a sixth intravesical drug delivery system into the bladder in week 15 after removing the fifth intravesical drug delivery system, and removing the sixth intravesical drug delivery system in week 18; vii) inserting a seventh intravesical drug delivery system into the bladder in week 18 after removing the sixth intravesical drug delivery system, and removing the seventh intravesical drug delivery system in week 21; viii) inserting an eighth intravesical drug delivery system into the bladder in week 21 after removing the seventh intravesical drug delivery system, and removing the eighth intravesical drug delivery system in week 24; wherein each intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.

47. The method of any one of claims 1-12, and 15-46, further comprising a maintenance phase, wherein the maintenance phase comprises administering about 225 mg gemcitabine to the bladder of the individual for about three weeks about every three months.

48. The method of claim 47, wherein the maintenance phase begins about 36 weeks after the start of treatment with gemcitabine.

49. The method of claim 47 or claim 48, wherein the maintenance phase comprises administering about 225 mg gemcitabine to the bladder of the individual during weeks 36-39, 48-51, 60-63, 72-75, 84-87, or 96-99.

50. The method of any one of claims 47-49, comprising i) inserting an intravesical drug delivery system into the bladder of the individual on about week 36 and removing the intravesical drug delivery system on about week 39;ii) inserting an intravesical drug delivery system into the bladder of the individual on about week 48 and removing the intravesical drug delivery system on about week 51; iii) inserting an intravesical drug delivery system into the bladder of the individual on about week 60 and removing the intravesical drug delivery system on about week 63; iv) inserting an intravesical drug delivery system into the bladder of the individual on about week 72 and removing the intravesical drug delivery system on about week 75; v) inserting an intravesical drug delivery system into the bladder of the individual on about week 84 and removing the intravesical drug delivery system on about week 87; vi) inserting an intravesical drug delivery system into the bladder of the individual on about week 96 and removing the intravesical drug delivery system on about week 99; wherein the intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.

51. The method of any one of claims 1-50, comprising a dosing schedule of at least 99 weeks comprising i) inserting a first intravesical drug delivery system into the bladder in week 0, and removing the first intravesical drug delivery system in week 3; ii) inserting a second intravesical drug delivery system into the bladder in week 3 after removing the first intravesical drug delivery system, and removing the second intravesical drug delivery system in week 6; iii) inserting a third intravesical drug delivery system into the bladder in week 6 after removing the second intravesical drug delivery system, and removing the third intravesical drug delivery system in week 9; iv) inserting a fourth intravesical drug delivery system into the bladder in week 9 after removing the third intravesical drug delivery system, and removing the fourth intravesical drug delivery system in week 12; v) inserting a fifth intravesical drug delivery system into the bladder in week 12 after removing the fourth intravesical drug delivery system, and removing the fifth intravesical drug delivery system in week 15; vi) inserting a sixth intravesical drug delivery system into the bladder in week 15 after removing the fifth intravesical drug delivery system, and removing the sixth intravesical drug delivery system in week 18;vii) inserting a seventh intravesical drug delivery system into the bladder in week 18 after removing the sixth intravesical drug delivery system, and removing the seventh intravesical drug delivery system in week 21; viii) inserting an eighth intravesical drug delivery system into the bladder in week 21 after removing the seventh intravesical drug delivery system, and removing the eighth intravesical drug delivery system in week 24; ix) inserting a ninth intravesical drug delivery system into the bladder in week 36, and removing the ninth intravesical drug delivery system in week 39; x) inserting a tenth intravesical drug delivery system into the bladder in week 48, and removing the tenth intravesical drug delivery system in week 51; xi) inserting an eleventh intravesical drug delivery system into the bladder in week 60, and removing the eleventh intravesical drug delivery system in week 63; xii) inserting a twelfth intravesical drug delivery system into the bladder in week 72, and removing the twelfth intravesical drug delivery system in week 75; xiii) inserting a thirteenth intravesical drug delivery system into the bladder in week84, and removing the thirteenth intravesical drug delivery system in week 87; xiv) inserting a fourteenth intravesical drug delivery system into the bladder in week96, and removing the fourteenth intravesical drug delivery system in week 99; wherein each intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.

52. The method of any one of claims 1-51, comprising i) deploying an intravesical drug delivery system into the bladder once every 3 weeks over approximately 6 months; followed by ii) deploying an intravesical drug delivery system into the bladder once every 12 weeks over approximately 18 months; wherein each intravesical drug delivery system is removed 3 weeks after each administration.

53. The method of claims 52, wherein the method comprises deploying a total of about 14 intravesical drug delivery systems over about 2 years.

54. The method of any one of claims 10-12, or 18-53, wherein the concentration of gemcitabine in the urine is from about 1 pg / mL to about 25 pg / mL or from about 4 pg / mL to about 50 pg / mL during the delivery period.

55. The method of any one of claims 4, 8, 10, 13, or 45-54, wherein the intravesical drug delivery system releases gemcitabine at a rate of about 10 mg / day to about 45 mg / day for the first seven days of administration.

56. The method of any one of claims 4, 8, 10, 13, or 45-55, wherein the concentration of gemcitabine in the urine reaches a maximum concentration between about 2 to about 4 days following administration of the gemcitabine.

57. The method of any one of claims 4, 8, 10, 13, or 45-56, wherein the intravesical drug delivery system releases gemcitabine to produce a mean cumulative excreted gemcitabine in urine value expressed as percentage of the administered dose from 0-168 hours from between about 36% to about 54%.

58. The method of any one of claims 4, 8, 10, 13, or 45-57, wherein the intravesical drug delivery system releases gemcitabine to produce a mean cumulative excreted dFdU amount in urine value expressed as percentage of the administered dose from 0-168 hours from between about 11% to about 23.3%.

59. The method of claim 15, wherein during each administration period the intravesical drug delivery system releases about 90% of the about 225 mg gemcitabine.

60. The method of claim 18, wherein during each delivery period the intravesical drug delivery system releases about 70% of the about 225 mg of gemcitabine.

61. The method of any one of claims 4, 8, 10, 13, or 45-60, wherein the intravesical drug delivery system releases gemcitabine during a first phase of the delivery at a first release rate followed by a second phase of the delivery having a second release rate.

62. The method of any one of claims 4, 8, 10, 13, or 45-61, wherein the intravesical drug delivery system comprises an intravesical device that comprises a housing which contains and controllably releases the gemcitabine and is elastically deformable between a retention shape configured to retain the intravesical device in the individual’s bladder and a deployment shape for passage of the intravesical device through the individual’s urethra.

63. The method of any one of claims 1-62, wherein the median duration of response in the population of patients is not reached within about 10.6 months.

64. The method of any one of claims 1-63, wherein the median duration of response in the population of patients is not reached within about 48 weeks.

65. The method of any one of claims 1-64, wherein such treatment results in a 6-month event- free survival in the population of patients between about 69% to about 95%.

66. The method of any one of claims 1-65, wherein such treatment results in a 12-month event-free survival in the population of patients between about 50% to about 88%.

67. The method of any one of claims 1-66, wherein such treatment results in an 18-month event-free survival in the population of patients between about 50% to about 88%.

68. The method of any one of claims 1-67, wherein such treatment results in a 24-month event-free survival in the population of patients between about 50% to about 88%.

69. A kit comprising an intravesical drug delivery system comprising about 225 mg of gemcitabine and instructions for use comprising the method of any one of claims 1-68.

70. The kit of claim 69, further comprising a urinary placement catheter.

71. An article of manufacture comprising an intravesical drug delivery system comprising an intravesical device comprising about 225 mg of gemcitabine and a package insert comprising instructions for use according to the method of any one of claims 1-68.

72. An intravesical drug delivery system comprising an intravesical device comprising about 225 mg gemcitabine for use in the method of any one of claims 1-68.

73. Gemcitabine for use according to the method of any one of claims 1-68.

74. Use of gemcitabine for treating high-risk non-muscle invasive bladder cancer (HR- NMIBC) that is unresponsive to intravesical Bacillus Calmette-Guerin (BCG) therapy in an individual comprising administering to the bladder of the individual about 225 mg of gemcitabine about every three weeks (Q3W) for at least about 24 weeks, wherein such treatment results in a complete response rate in a population of patients who have received such treatment of at least 50%.

75. The method of any one of claims 1-68, wherein the gemcitabine is gemcitabine free base equivalent (FBE).

76. The method of any one of claims 1-68, or 75, wherein a) less than about 91% of individuals within the population of patients experience an adverse effect; b) less than about 35% of individuals within the population of patients experience a greater than grade 3 adverse effect;c) less than about 40% of individuals within the population of patients experience micturition urgency; d) less than about 40% of individuals within the population of patients experience pollakiuria; e) less than about 30% of individuals within the population of patients experience noninfective cystitis; f) less than about 30% of individuals within the population of patients experience a urinary tract infection; g) less than about 5% of individuals within the population of patients experience pruritus; h) less than about 5% of individuals within the population of patients experience diarrhea; i) less than about 30% of individuals within the population of patients experience dysuria; j) less than about 15% of individuals within the population of patients experience hematuria; k) less than about 10% of individuals within the population of patients experience urinary tract pain; l) less than about 10% of individuals within the population of patients experience urinary retention; m) less than about 5% of individuals within the population of patients experience renal impairment; and / or n) less than about 5% of individuals within the population of patients experience urosepsis.

77. Minitablets comprising gemcitabine for use according to the method of any one of claims 1-68, 75, or 76.

78. The method of any one of claims 1-68, 75, or 76, wherein the individual is elderly and / or frail.

79. The method of any one of claims 4, 8, 10, 13, 45-68, 75, 76, or 78, wherein the intravesical drug delivery system is a TAR- 200 intravesical drug delivery system.

80. The method of any one of claims 1-68, 75, 76, 78, or 79, wherein the median duration of response in the population of patients is about 26 months.

81. The method of any one of claims 1-68, 75, 76, or 78-80, wherein such treatment results in a one-year duration of response (DOR) rate in the population of patients of at least 50%.

82. The method of claim 81, wherein one-year duration of response (DOR) rate in the population of patients is between about 50% to about 89%.

83. The method of claim 81 or claim 82, wherein the one-year DOR rate is about 77%.

84. The method of any one of claims 1-68, 75, 76, or 78-83, wherein such treatment results in a 12-month CR rate in the population of patients of at least 40%.

85. The method of claim 84, wherein the 12-month CR rate in the population of patients is between about 43% to about 79%.

86. The method of claim 84 or claim 85, wherein the 12-month CR rate in the population of patients is about 64%.

87. The method of any one of claims 1-68, 75, 76, or 78-86, wherein such treatment results in a 15-month CR rate in the population of patients of at least 40%.

88. The method of claim 87, wherein the 15-month CR rate in the population of patients is between about 43% to about 79%.

89. The method of claim 87 or claim 88, wherein the 15-month CR rate in the population of patients is about 64%.

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