Neoadjuvant therapy for bladder cancer

Abstract

This invention relates to a neoadjuvant therapy for bladder cancer in bladder cancer patients who are scheduled for a cystectomy and methods of carrying out such a neoadjuvant therapy. In particular, the invention relates to a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a neoadjuvant therapy for bladder cancer in a bladder cancer patient who is scheduled for a cystectomy, the therapy comprises instilling said composition into the bladder of said patient and exposing the inside of said bladder to light.

Claims

1. A method of neoadjuvant therapy for muscular invasive bladder cancer (MIBC) or non-muscular invasive bladder cancer (NMIBC) with a high risk of progression in a bladder cancer patient who is scheduled for a cystectomy, said method of neoadjuvant therapy comprises: instilling into the bladder of said patient who is scheduled for a cystectomy a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof; and exposing the inside of said bladder to light; wherein the time between said neoadjuvant therapy and the cystectomy is zero to 4 weeks.

2. The neoadjuvant therapy according to claim 1, wherein the bladder cancer is muscular invasive bladder cancer (MIBC).

3. The neoadjuvant therapy according to claim 1, wherein the bladder cancer is NMIBC with a high risk of progression.

4. The neoadjuvant therapy according to claim 1, wherein the composition comprises a pharmaceutically acceptable salt of HAL.

5. The neoadjuvant therapy according to claim 4, wherein the composition comprises the hydrochloride salt of HAL.

6. The neoadjuvant therapy according to claim 1, wherein the composition comprises HAL in the range of 0.1 to 5% by weight of the total weight of the composition or the equivalent concentration of a pharmaceutically acceptable salt of HAL.

7. The neoadjuvant therapy according to claim 1, wherein the composition is a semi-solid composition or a liquid composition.

8. The neoadjuvant therapy according to claim 1, wherein the composition is liquid composition comprising a liquid carrier.

9. The neoadjuvant therapy according to claim 8, wherein the liquid carrier water or an aqueous buffer.

10. The neoadjuvant therapy according to claim 9, wherein the aqueous buffer is a phosphate buffer.

11. The neoadjuvant therapy according to claim 1, wherein the composition is a liquid composition comprising hexyl 5-ALA ester hydrochloride at a concentration of 0.2% in an aqueous phosphate buffer comprising disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

12. The neoadjuvant therapy according to claim 1, wherein the composition is instilled into the bladder through a catheter and left in the bladder from about 20 minutes to about 3 hours.

13. The neoadjuvant therapy according to claim 1, wherein at least 1 hour is allowed to pass from the instillation of the composition into the bladder to the start of exposing the inside of the bladder to light.

14. The neoadjuvant therapy according claim 1, wherein the inside of the bladder is exposed to white light and/or blue light and/or red light.

15. The neoadjuvant therapy according claim 14, wherein the inside of the bladder is exposed to red light.

16. The neoadjuvant therapy according to claim 14, wherein the inside of the bladder is exposed to white light and blue light.

17. The neoadjuvant therapy according to claim 16, wherein the inside of the bladder is exposed to white light followed by blue light.

18. The neoadjuvant therapy according to claim 1, wherein said neoadjuvant therapy is carried out prior, simultaneously or after other neoadjuvant therapies.

19. The neoadjuvant therapy according to claim 1, wherein said composition further comprises anti-PD-L1 antibodies and/or anti-PD-1 antibodies.

20. The neoadjuvant therapy according to claim 19, wherein said composition comprises anti-PD-L1 antibodies or anti-PD-1 antibodies.

21. The neoadjuvant therapy according to claim 1, wherein the time between the neoadjuvant therapy and the cystectomy is zero to 3 weeks.

22. The neoadjuvant therapy according to claim 1, wherein the time between the neoadjuvant therapy and the cystectomy is zero to 2 weeks.

23. The neoadjuvant therapy according to claim 1, wherein the time between the neoadjuvant therapy and the cystectomy is zero to 1 week.

Description

EMBODIMENT 1

(1) Composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a neoadjuvant therapy for bladder cancer in a bladder cancer patient who is scheduled for a cystectomy, the therapy comprises instilling said composition into the bladder of said patient and exposing the inside of said bladder to light.

EMBODIMENT 2

(2) Composition for use according to embodiment 1, wherein the bladder cancer is muscular invasive bladder cancer (MIBC).

EMBODIMENT 3

(3) Composition for use according to embodiment 1, wherein the bladder cancer is non-muscular invasive bladder cancer (NMIBC).

EMBODIMENT 4

(4) Composition for use according to embodiment 3, wherein the bladder cancer is NMIBC with a high risk of progression.

EMBODIMENT 5

(5) Composition for use according to any of the preceding embodiments, wherein the composition comprises a pharmaceutically acceptable salt of HAL.

EMBODIMENT 6

(6) Composition for use according to embodiment 5, wherein the composition comprises the hydrochloride salt of HAL.

EMBODIMENT 7

(7) Composition for use according to any of the preceding embodiments, wherein the composition comprises HAL in the range of 0.1 to 5% by weight of the total weight of the composition or the equivalent concentration of a pharmaceutically acceptable salt of HAL.

EMBODIMENT 8

(8) Composition for use according to any of the preceding embodiments, wherein the composition is a semi-solid composition or a liquid composition.

EMBODIMENT 9

(9) Composition for use according to any of the preceding embodiments, wherein the composition is liquid composition comprising a liquid carrier, preferably water, an aqueous solution or an aqueous buffer, preferably a phosphate buffer.

EMBODIMENT 10

(10) Composition for use according to any of the preceding embodiments, wherein the composition is a liquid composition comprising hexyl 5-ALA ester hydrochloride at a concentration of 0.2% in an aqueous phosphate buffer comprising disodium phosphate dehydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

EMBODIMENT 11

(11) Composition for use according to any of the preceding embodiments, wherein the composition is instilled into the bladder through a catheter and left in the bladder from about 20 minutes to about 3 hours.

EMBODIMENT 12

(12) Composition for use according to any of the preceding embodiments, wherein at least 1 hour is allowed to pass from the instillation of the composition into the bladder to the start of exposing the inside of the bladder to light.

EMBODIMENT 13

(13) Composition for use according to any of the preceding embodiments, wherein the inside of the bladder is exposed to white light and/or blue light and/or red light.

EMBODIMENT 14

(14) Composition for use according to embodiment 13, wherein the inside of the bladder is exposed to white light followed by blue light.

EMBODIMENT 15

(15) Composition for use according to any of the preceding embodiments, wherein the time between said neoadjuvant therapy and the cystectomy is zero to 6 weeks.

EMBODIMENT 16

(16) Composition for use according to any of the preceding embodiments, wherein said neoadjuvant therapy is carried out prior, simultaneously or after other neoadjuvant therapies.

EMBODIMENT 17

(17) Composition for use according to any of the preceding embodiments, wherein said composition further comprises anti-PD-L1 antibodies and/or anti-PD-1 antibodies.

EMBODIMENT 18

(18) Composition for use according to embodiment 17, wherein said composition comprises anti-PD-L1 antibodies.

EMBODIMENT 19

(19) Composition for use according to embodiment 17, wherein said composition comprises anti-PD-1 antibodies.

EMBODIMENT 20

(20) Composition for use according to embodiment 17 wherein said composition comprises anti-PD-L1 antibodies and. anti-PD-1 antibodies.

EMBODIMENT 21

(21) A neoadjuvant therapy for bladder cancer in a bladder cancer patient who is scheduled for a cystectomy, said therapy comprises instilling into the bladder of said patient a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof and exposing the inside of said bladder to light.

EMBODIMENT 22

(22) Neoadjuvant therapy according to embodiment 21, wherein the bladder cancer is muscular invasive bladder cancer (MIBC).

EMBODIMENT 23

(23) Neoadjuvant therapy according to embodiment 21, wherein the bladder cancer is non-muscular invasive bladder cancer (NMIBC).

EMBODIMENT 24

(24) Neoadjuvant therapy according to embodiment 23, wherein the bladder cancer is NMIBC with a high risk of progression.

EMBODIMENT 25

(25) Neoadjuvant therapy according to any of the preceding embodiments, wherein the composition comprises a pharmaceutically acceptable salt of HAL.

EMBODIMENT 26

(26) Neoadjuvant therapy according to embodiment 25, wherein the composition comprises the hydrochloride salt of HAL.

EMBODIMENT 27

(27) Neoadjuvant therapy according to any of the preceding embodiments, wherein the composition comprises HAL in the range of 0.1 to 5% by weight of the total weight of the composition or the equivalent concentration of a pharmaceutically acceptable salt of HAL.

EMBODIMENT 28

(28) Neoadjuvant therapy according to any of the preceding embodiments, wherein the composition is a semi-solid composition or a liquid composition.

EMBODIMENT 29

(29) Neoadjuvant therapy according to any of the preceding embodiments, wherein the composition is liquid composition comprising a liquid carrier, preferably water, an aqueous solution or an aqueous buffer, preferably a phosphate buffer.

EMBODIMENT 30

(30) Neoadjuvant therapy according to any of the preceding embodiments, wherein the composition is a liquid composition comprising hexyl 5-ALA ester hydrochloride at a concentration of 0.2% in an aqueous phosphate buffer comprising disodium phosphate dehydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

EMBODIMENT 31

(31) Neoadjuvant therapy according to any of the preceding embodiments, wherein the composition is instilled into the bladder through a catheter and left in the bladder from about 20 minutes to about 3 hours.

EMBODIMENT 32

(32) Neoadjuvant therapy according to any of the preceding embodiments, wherein at least 1 hour is allowed to pass from the instillation of the composition into the bladder to the start of exposing the inside of the bladder to light.

EMBODIMENT 33

(33) Neoadjuvant therapy according to any of the preceding embodiments, wherein the inside of the bladder is exposed to white light and/or blue light and/or red light.

EMBODIMENT 34

(34) Neoadjuvant therapy according to embodiment 33, wherein the inside of the bladder is exposed to white light followed by blue light.

EMBODIMENT 35

(35) Neoadjuvant therapy according to any of the preceding embodiments, wherein the time between said neoadjuvant therapy and the cystectomy is zero to 6 weeks.

EMBODIMENT 36

(36) Neoadjuvant therapy according to any of the preceding embodiments, wherein said neoadjuvant therapy is carried out prior, simultaneously or after other neoadjuvant therapies.

EMBODIMENT 37

(37) Neoadjuvant therapy according to any of the preceding embodiments, wherein said composition further comprises anti-PD-L1 antibodies and/or anti-PD-1 antibodies.

EMBODIMENT 38

(38) Neoadjuvant therapy according to embodiment 37, wherein said composition comprises anti-PD-L1 antibodies.

EMBODIMENT 39

(39) Neoadjuvant therapy according to embodiment 37, wherein said composition comprises anti-PD-1 antibodies.

EMBODIMENT 40

(40) Neoadjuvant therapy according to embodiment 37 wherein said composition comprises anti-PD-L1 antibodies and. anti-PD-1 antibodies.