Novel adjuvant therapy for bladder cancer

Abstract

The present invention relates to neoadjuvant therapies for bladder cancer in bladder cancer patients scheduled for bladder resection and methods of implementing such neoadjuvant therapies. Specifically, the present invention relates to a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a neoadjuvant therapy of bladder cancer in a bladder cancer patient scheduled for bladder resection, the therapy comprising dripping said composition into the bladder of said patient and exposing the interior of said bladder to light.

Description

[0001] This application is a divisional application of the invention patent application with application number 201680079674.2, application date December 19, 2016, and invention name “Neoadjuvant therapy for bladder cancer”.

[0002] The present invention relates to neoadjuvant therapy for bladder cancer in bladder cancer patients scheduled for cystectomy and methods of implementing such neoadjuvant therapy.

[0003] Bladder cancer is the ninth most common cancer diagnosis worldwide, with more than 330,000 new cases and more than 130,000 deaths each year. At any given time, 2.7 million people have a history of urinary bladder cancer.

[0004] The diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder (cystoscopy) and histologic evaluation of the excised tissue. Generally, cystoscopy is initially performed in the office, using flexible instruments. At the time of the initial diagnosis of bladder cancer, 70% of cases are diagnosed as non-muscle invasive bladder cancer (NMIBC), and approximately 30% are diagnosed as muscle invasive bladder cancer (MIBC).

[0005] If a bladder tumor has been detected during cystoscopy, the patient will undergo a transurethral resection (TUR), a procedure to visualize the bladder through the urethra and remove the tumor and lesions. In the case of NMIBC, this resection will completely remove the tumor, while in the case of MIBC, this resection is palliative. In addition to tumor resection, TUR is performed so that the pathologist can make a correct histological diagnosis of the removed tumor / tumor biopsy.

[0006] For patients with MIBC, the standard treatment is radical cystectomy, which is the removal of the bladder and adjacent organs, namely the prostate and seminal vesicles in men, and the uterus and adnexa in women. It also includes the removal of regional lymph nodes. Cystectomy is also advocated for patients with NMIBC who are at high risk of progression, that is, patients with multiple recurrent high-grade tumors, high-grade T1 tumors, or high-grade tumors with carcinoma in situ (CIS). In addition, cystectomy is advocated for NMIBC patients who have received Bacillus Calmette-Guérin (BCG) immunotherapy but have failed this treatment.

[0007] Despite being the gold standard for MIBC treatment and advocated in certain types of NMIBC patients, radical cystectomy provides 5-year survival in only about 50% of patients. To improve these unsatisfactory outcomes, the use of neoadjuvant therapy, i.e. therapy given before / before primary treatment with cystectomy, has been explored since the 1980s.

[0008] Neoadjuvant radiotherapy has been used, but tumor downgrading after such radiotherapy takes approximately 4–6 weeks. Furthermore, procedural delays of more than 90 days in patients with locally advanced bladder cancer have been shown to result in a significant increase in extravesical disease (81 vs. 52%). According to current European guidelines for MIBC, neoadjuvant radiotherapy is not recommended because there are no data to support increased survival with neoadjuvant radiotherapy for operable MIBC.

[0009] There are many advantages to neoadjuvant chemotherapy, including administration of chemotherapy at the earliest possible time point when the burden of micrometastatic disease is expected to be low; the expected better tolerability of chemotherapy before cystectomy than after cystectomy; and the assumption that patients with micrometastatic disease may respond to neoadjuvant therapy and therefore demonstrate favorable pathologic status as determined primarily by negative nodal status and negative procedural margins. Neoadjuvant cisplatin-containing chemotherapy has been shown to significantly improve survival (5% absolute improvement in 5-year survival). However, as noted above, delayed cystectomy may affect outcomes in patients who are chemotherapy-insensitive, and in general, preoperative anemia and neuropathy are more common in patients who receive neoadjuvant chemotherapy before cystectomy. Current European guidelines for MIBC state that “….neoadjuvant chemotherapy has its limitations in terms of patient selection, current developments in procedural technology, and current chemotherapy combinations.” Therefore, there is room for improvement in the neoadjuvant treatment of patients with bladder cancer scheduled for cystectomy.

[0010] Therefore, we recommend that bladder cancer patients scheduled for cystectomy receive neoadjuvant therapy comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder and exposing the interior of the bladder to light.

[0011] In the treatment of bladder cancer, instilling a composition including HAL or a pharmaceutically acceptable salt thereof into the patient's bladder and exposing the interior of the bladder to blue light can be used to improve the visualization of bladder cancer during cystoscopy and / or TUR. As a standard procedure, cystoscopy and TUR are performed using white light. However, since the use of white light can lead to missing lesions that exist but are not visible, photodynamic diagnosis (PDD) is often used in this procedure. PDD involves administering a photosensitizer or its precursor (i.e., a "photosensitizer") to the target area. The photosensitizer or its precursor is absorbed into the cell, where the precursor of the photosensitizer is converted into an active photosensitizer. When the target area is exposed to light of a suitable wavelength, the photosensitizer is excited, and when relaxed to its ground state, fluorescence occurs.

[0012] 5-ALA hexyl ester (hexaminolevulinate, HAL) and its salts are such photosensitizers. HAL preferably penetrates rapidly proliferating cells, such as tumor cells, where it is converted into porphyrins, which are photosensitizers and fluorescent compounds. Under subsequent irradiation with blue light, porphyrins emit red light, thereby enabling specific and accurate visualization of tumors. (Photocure ASA, Norway and Ipsen SA, France) is a marketed approved drug that includes HAL and is used for PDD during cystoscopy and TUR procedures.

[0013] In NMIBC patients, HAL-guided cystoscopy and TUR have improved the detection of papillary tumors and flat carcinoma in situ (CIS) lesions, which are difficult to detect with white light alone. In NMIBC patients, compared with white light TUR alone, HAL-guided bladder cancer TUR has also reduced the residual tumor rate after such surgery, and has led to a better recurrence-free survival (RFS) rate and extended RFS interval (see Rink M et al., Eur Urol 4 (64), 2013, 624). Existing European NMIBC guidelines and consensus statements of several expert groups recommend the use of HAL-guided TUR in various settings for NMIBC treatment, and some even recommend using it in all NMIBC patients at the time of initial TUR (see Witjes JA et al., Eur Urol 1 (66), 2014, 863).

[0014] Also in MIBC patients, HAL-guided TUR affects recurrence-free survival: In 268 consecutive patients undergoing cystectomy, it was retrospectively investigated whether the patient underwent HAL-guided TUR before cystectomy, or whether TUR was performed only under white light. Kaplan-Meier analysis was used to evaluate recurrence-free survival (RFS) and overall survival (OS). The 3-year RFS was 69.8% in patients with HAL-guided TUR and 58.2% in patients with white light TUR alone. The 3-year OS was 65.0% and 56.6% in patients with HAL-guided TUR. These results indicate that HAL-guided TUR is associated with improved RFS after cystectomy in patients with MIBC (see G. Gakis et al., Urology Vol. 82, Issue 3, Supplement, Unmoderated Posters, UP. 046).

[0015] The residual tumor rate and detection of all tumor lesions in the bladder during TUR in patients with MIBC are not an issue because the bladder is removed en bloc anyway. Therefore, TUR in patients with MIBC is usually performed with white light only, and there is no guideline recommendation for the use of HAL guidance in this TUR.

[0016] Clearly, given its current use in bladder cancer treatment, it is surprising that HAL could be used as a neoadjuvant therapy for bladder cancer patients scheduled for cystectomy.

[0017] HAL has several advantages over the above-mentioned neoadjuvant radiotherapy or chemotherapy, among which nausea, vomiting, fatigue, anemia, epithelial surface damage, intestinal discomfort / gastrointestinal irritation, nephrotoxicity, neurotoxicity, swelling, immune system suppression and infertility are well-known and common side effects. In contrast, most of the reported adverse reactions of HAL (in the form of The effects are short-lived and range from mild to moderate in intensity. The most common adverse reactions were bladder spasm, reported by 2.4% of patients, dysuria (1.8%), bladder pain (1.7%), and hematuria (1.7%).

[0018] Moreover, HAL has a very favorable metabolic profile compared to neoadjuvant chemotherapy drugs such as cisplatin. HAL interferes with the body's own heme biosynthesis pathway and leads to the accumulation of photoactive porphyrins, especially protoporphyrin IX (PpIX), the final intermediate of heme synthesis. Since this photoactive porphyrin is a naturally occurring compound in the body, there is a "natural process" in the body to degrade (metabolize) and secrete the degraded heme.

[0019] Thus, in a first aspect, the present invention provides a neoadjuvant therapy for bladder cancer in a bladder cancer patient scheduled for cystectomy, the therapy comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of the patient and exposing the interior of the bladder to light.

[0020] In an alternative first aspect, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in neoadjuvant therapy of bladder cancer in a bladder cancer patient scheduled for cystectomy, the therapy comprising instilling the composition into the patient's bladder and exposing the interior of the bladder to light.

[0021] Bladder cancer in the context of the present invention is muscle invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC). In the latter case, NMIBC is a cancer with a high risk of progression, including multiple recurrent high-grade tumors or high-grade T1 tumors or high-grade tumors with concurrent carcinoma in situ (CIS).

[0022] The term "neoadjuvant therapy" refers to the administration of a therapeutic agent prior to / before the primary treatment of the disease. In the context of the present invention, the primary treatment is cystectomy and the disease is bladder cancer, ie MIBC or NMIBC.

[0023] The term "5-ALA" means 5-aminolevulinic acid, 5-amino-4-oxo-pentanoic acid.

[0024] The term "5-ALA hexyl ester" (HAL) means n-hexyl aminolevulinate, ie n-hexyl 5-amino-4-oxo-pentanoate.

[0025] The term "pharmaceutically acceptable salts" denotes salts which are suitable for use in dry drug products and meet requirements relating to, for example, safety, bioavailability and tolerability (see, for example, PH Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002).

[0026] The synthesis of 5-ALA hexyl ester is known in the art and can be prepared as described, for example, in WO 96 / 28412, the entire contents of which are incorporated herein by reference. Briefly, 5-ALA hexyl ester can be prepared by reacting 5-ALA with hexanol in the presence of a catalyst, such as an acid. In addition, 5-ALA hexyl ester hydrochloride is commercially available, for example, as (Photocure ASA and Ipsen Pharma SA) or (Photocure Corporation) form.

[0027] The 5-ALA hexyl ester used in embodiments of the present invention is preferably in the form of a pharmaceutically acceptable salt. Such salts are preferably acid addition salts of pharmaceutically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric acid, nitric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfonic acid and sulfonic acid derivatives, and salts of ALA-esters and the latter acids are described in WO 2005 / 092838 to Photocure ASA, the entire contents of which are incorporated herein by reference. The preferred acid is hydrochloric acid, HCl. Synthetic processes for salt formation are conventional in the art, for example, in WO 2005 / 092838.

[0028] The concentration of HAL in the composition for use in the present invention is suitably 0.1 to 5% by weight of the total weight of the composition or an equivalent concentration of a pharmaceutically acceptable salt of HAL, preferably 0.15 to 3.5%, and most preferably 0.17% (e.g. corresponding to 0.2% HAL hydrochloride).

[0029] The composition used in the present invention may include a pharmaceutically acceptable carrier, excipient or stabilizer. The composition used in the present invention is preferably a semi-solid composition or a liquid composition. The term "semi-solid" refers to a physical state that is neither solid nor liquid. Semi-solids (or quasi-solids) are similar to solids in some respects, such as semi-solids that can support their own weight and maintain their shape, but also share some properties of liquids, such as shapes that conform to objects that apply pressure to them, or the ability to flow under pressure. Semi-solids are characterized by a three-dimensional structure that is sufficient to give undisturbed systems solid-like properties, but are easily decomposed and rearranged under applied forces. Semi-solids have rigidity and viscosity between solids and liquids. Preferred semi-solid compositions are foams, gels and lotions, preferably low-viscosity gels and lotions. However, liquid compositions are preferred, particularly liquid compositions of solutions or suspensions of HAL in liquid carriers. Preferred liquid carriers are water or aqueous solutions, and the most preferred liquid carriers are aqueous buffers.

[0030] The composition used in the present invention may comprise a pharmaceutically acceptable excipient, including an emulsifier, a mucoadhesive agent, a surface penetrant or a chelating agent (see, for example, WO 2010 / 142457).

[0031] In a preferred embodiment, the composition used in the present invention is a liquid composition comprising a liquid carrier, more preferably water or an aqueous solution, most preferably an aqueous buffer, preferably a phosphate buffer. In a particularly preferred embodiment, the composition used in the present invention comprises an aqueous phosphate buffer as a liquid carrier, more preferably a phosphate buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0032] In a particularly preferred embodiment, the composition for use in the present invention is That is, a solution of 5-HAL hexyl ester hydrochloride (2 mg / ml; 0.2%) in an aqueous buffer solution comprising dehydrated disodium phosphate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0033] In a preferred embodiment, HAL or a pharmaceutically acceptable salt thereof is provided in lyophilized form and reconstituted in a liquid carrier, preferably water or an aqueous solution, most preferably an aqueous buffer, prior to use.

[0034] If the composition used in the present invention is a liquid composition comprising water, the pH of the composition is preferably in the range of 4.5 to 7.5, more preferably the pH is in the range of 5.7 to 7.2.

[0035] The amount of the composition instilled into the bladder can vary depending on the volume of the patient's bladder and the size of the bladder. As observed, a volume of about 50 ml of the composition is suitable and sufficient.

[0036] The composition used in the present invention is preferably instilled into the empty bladder through a catheter (preferably a catheter that is part of a cystoscope) and retained in the bladder for about 20 minutes to about 3 hours, more preferably about 30 minutes to about 2 hours, and most preferably not less than 1 hour, such as 1 hour. If the patient cannot retain the composition for 1 hour, at least 1 hour should be allowed to pass from the instillation of the composition into the bladder to the start of exposing the interior of the bladder to light.

[0037] To expose the interior of the bladder to light, any wavelength of light suitable for exciting 5-ALA hexyl ester can be used. Preferred are white light, i.e. visible light with a wavelength of about 350 to 700 nm, and / or blue light, i.e. a wavelength of about 360 nm to about 450 nm, and / or red light, i.e. a wavelength of about 600 to 670 nm. The term "and / or" means, for example, that the interior of the bladder is exposed to either white light or blue light or white light and blue light (subsequently but not simultaneously). Particularly preferred are white light and / or blue light, more preferred are white light followed by blue light. Thus, in one embodiment, the interior of the bladder is first exposed to white light and then subsequently to blue light.

[0038] In a preferred first embodiment, the neoadjuvant therapy of the present invention comprises a) That is, a solution of 5-ALA hexyl ester hydrochloride (2 mg / ml; 0.2%) in an aqueous buffer comprising dehydrated sodium phosphate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water is dropped into the bladder of a patient scheduled for cystectomy, preferably in a volume of 50 ml, and b) the interior of the bladder is exposed to white light and then subsequently to blue light.

[0039] In an alternative preferred first embodiment, the present invention provides A solution of 5-ALA hexyl ester hydrochloride (2 mg / ml; 0.2%) in an aqueous buffer solution comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water for use in neoadjuvant therapy of bladder cancer in patients with bladder cancer scheduled for cystectomy, the therapy comprising a) instilling into the patient's bladder, and b) exposing the interior of the bladder to white light and then to blue light.

[0040] In order to expose the interior of the bladder to light, an approved cystoscope light source that allows white and blue light illumination of the interior of the bladder is preferred. Such cystoscopes are commercially available, for example from Karl Storz (Photodynamic Diagnosis D-Light C (PDD) System), Olympus or Richard Wolf). For red light illumination, such equipment can be modified with suitable filters. Such cystoscope light sources can be rigid or flexible.

[0041] The light dose given during irradiation of the interior of the bladder with white light and blue light may vary, but is preferably 0.01 to 100 J / cm 2 , more preferably 0.03-40 J / cm 2 , most preferably 0.1 to 3 J / cm 2 For cystoscopic light sources with an output in the range of 47-82 mW, such a light dose is provided in approximately 10 to 30 minutes (based on a human bladder of 300 cm 2 surface area calculation).

[0042] The time between the neoadjuvant therapy of the present invention (i.e., instilling a composition comprising HAL into the bladder and exposing the interior of the bladder to light) and cystectomy can vary, but is preferably 0 to 6 weeks, such as 0 to 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks, more preferably 0 to 3 weeks, such as 1 week or 2 weeks. "Zero" means that cystectomy is performed directly after the light irradiation provided in the neoadjuvant method of the present invention is completed. The advantage is that the patient is anesthetized only once.

[0043] The neoadjuvant therapy of the present invention may be performed once or repeatedly, such as twice or more, such as 3, 4, 5 or 6 times, before cystectomy, with a time period between treatments of, for example, 4 days to 4 weeks, such as 1, 2 or 3 weeks.

[0044] The neoadjuvant therapy of the present invention can be performed before, simultaneously with, or after other neoadjuvant therapies, including neoadjuvant radiotherapy, neoadjuvant chemotherapy (bladder instillation or systemic administration) using, for example, cisplatin, methotrexate, vinblastine, valrubicin, doxorubicin, mitomycin C, or a combination thereof, and neoadjuvant immunotherapy (bladder instillation or systemic administration) using, for example, BCG.

[0045] A preferred neoadjuvant immunotherapy that can be performed before, simultaneously with, or after the neoadjuvant therapy of the present invention includes the use of an anti-PD-L1 antibody. Anti-PD-L1 is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. Anti-PD-L1 targets PD-L1 expressed on cancer cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, anti-PD-L1 can activate T cells, restoring their ability to effectively detect and attack cancer cells (e.g., bladder cancer cells).

[0046] Another preferred neoadjuvant immunotherapy may be performed before, simultaneously with, or after the neoadjuvant therapy of the present invention, including the use of anti-PD-1 antibodies. Anti-PD-1 is an investigational monoclonal antibody that binds to the PD-L1 (programmed death ligand 1) protein, which is present at high levels in many cancer types, such as bladder cancer. By competitively blocking the interaction with the PD-1 receptor, it is believed that anti-PD-1 thereby restores anti-cancer T cell responses.

[0047] Therefore, anti-PD-L1 antibodies and anti-PD-1 antibodies target different components of the same interaction mechanism between immune cells (especially killer T cells) and cancer cells, but have similar therapeutic effects: anti-PD-L1 antibodies target PD-L1 (programmed death ligand-1) expressed on cancer cells, while anti-PD-1 antibodies target the other half of the mechanism, namely PD-1 (programmed death receptor-1) expressed on killer T cells.

[0048] In a second aspect, the present invention provides a neoadjuvant therapy for bladder cancer in a bladder cancer patient scheduled for cystectomy, the therapy comprising a) instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder and exposing the interior of the bladder to light, and b) instilling a composition comprising an anti-PD-L1 antibody and / or an anti-PD-1 antibody into the patient's bladder.

[0049] In an alternative second aspect, the present invention provides a) a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, and b) a composition comprising an anti-PD-L1 antibody and / or an anti-PD-1 antibody, each for use in neoadjuvant therapy for bladder cancer in patients with bladder cancer scheduled for cystectomy, the neoadjuvant therapy comprising instilling a) into the patient's bladder and exposing the interior of the bladder to light, and instilling b) into the patient's bladder.

[0050] Embodiments and preferred embodiments of the second aspect of the invention are those described in the context of the first aspect of the invention.

[0051] Preferred anti-PD-L1 antibodies are those of Roche, preferably MPDL3280A. Such preferred anti-PD-L1 antibodies are described in WO 2010 / 077634, WO 2013 / 019906 and WO 2013 / 181452, the entire contents of which are incorporated herein by reference.

[0052] Preferred anti-PD-1 antibodies are antibodies from Merck, preferably pembrolizumab (Keytruda). Such preferred anti-PD-1 antibodies are described in WO 2008 / 156712, WO 2009 / 114335 and WO 2013 / 079174, the entire contents of which are incorporated herein by reference.

[0053] Other preferred anti-PD-1 antibodies are antibodies from Bristol-Myers Squibb, preferably nivolumab (Opdivo). Such preferred anti-PD-1 antibodies are described in WO 2004 / 004771, the entire contents of which are incorporated herein by reference.

[0054] Neoadjuvant therapy according to the present invention may be performed before, after, or after neoadjuvant therapy with anti-PD-L1 antibody and / or anti-PD-1 antibody.

[0055] Such antibodies may be formulated and administered as described in WO 2010 / 077634, WO 2013 / 019906 and WO 2013 / 181452 (anti-PD-L1 antibodies) or in WO 2004 / 004771, WO 2008 / 156712, WO 2009 / 114335 and WO 2013 / 079174 (anti-PD-1 antibodies), i.e., formulated as a formulation suitable for parenteral (e.g., subcutaneous) or intravenous administration. In a preferred embodiment, such anti-PD-L1 antibodies and / or anti-PD-1 antibodies are formulated for instillation into the bladder, preferably as a liquid composition. A preferred liquid composition is a solution or suspension of an anti-PD-L1 antibody and / or an anti-PD-1 antibody, i.e., more preferably comprises an anti-PD-L1 antibody and / or an anti-PD-1 antibody in a liquid carrier. A preferred liquid carrier is water or an aqueous solution, most preferably an aqueous buffer.

[0056] In a preferred embodiment, the anti-PD-L1 antibody and / or anti-PD-1 antibody is provided in lyophilized form and reconstituted in a liquid carrier, preferably water or an aqueous solution, most preferably an aqueous buffer, prior to use.

[0057] If the liquid composition comprises water, the pH of the composition is preferably in the range of 4.5 to 7.5.

[0058] In a preferred embodiment, the composition for the neoadjuvant therapy of the present invention includes a therapeutically effective amount of an anti-PD-L1 antibody and / or an anti-PD-1 antibody. This therapeutically effective amount can be administered by instillation into the bladder once or multiple times. For the purposes of the present invention, a therapeutically effective amount of an anti-PD-L1 antibody and / or an anti-PD-1 antibody is an amount sufficient to complete therapeutic treatment together with at least primary treatment, i.e., cystectomy. Other neoadjuvant therapies may be performed together with the neoadjuvant therapy of the present invention, such as neoadjuvant radiotherapy, neoadjuvant chemotherapy, or neoadjuvant immunotherapy.

[0059] After cystectomy, patients may receive adjuvant chemotherapy, such as cisplatin, methotrexate, vinblastine, doxorubicin, gemcitabine, doxorubicin, epirubicin, cyclophosphamide, or a combination thereof. Alternatively or in addition, patients may receive adjuvant immunotherapy, such as anti-PD-L1 antibodies.

[0060] In a third aspect, the present invention provides a composition comprising a) 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof and b) an anti-PD-L1 antibody and / or an anti-PD-1 antibody for use in neoadjuvant therapy of bladder cancer in patients with bladder cancer scheduled for cystectomy, the neoadjuvant therapy comprising instilling the composition into the patient's bladder and exposing the interior of the bladder to light.

[0061] In an alternative third aspect, the present invention provides a neoadjuvant therapy for bladder cancer in a bladder cancer patient scheduled for cystectomy, the therapy comprising instilling a composition comprising a) 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof and b) an anti-PD-L1 antibody and / or an anti-PD-1 antibody into the bladder of the patient, and exposing the interior of the bladder to light.

[0062] Embodiments and preferred embodiments of the third aspect of the invention are those described in the context of the first and second aspects of the invention.

[0063] Various embodiments of the present invention are as follows:

[0064] Embodiment 1: A composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in neoadjuvant therapy of bladder cancer in bladder cancer patients scheduled for cystectomy, the therapy comprising instilling the composition into the bladder of the patient and exposing the interior of the bladder to light.

[0065] Embodiment 2: The composition for use according to embodiment 1, wherein the bladder cancer is muscle invasive bladder cancer (MIBC).

[0066] Embodiment 3: The composition for use according to embodiment 1, wherein the bladder cancer is non-muscle invasive bladder cancer (NMIBC).

[0067] Embodiment 4: The composition for use according to embodiment 3, wherein the bladder cancer is NMIBC with a high risk of progression.

[0068] Embodiment 5: A composition for use according to any one of the preceding embodiments, wherein the composition comprises a pharmaceutically acceptable salt of HAL.

[0069] Embodiment 6: A composition for use according to embodiment 5, wherein the composition comprises the hydrochloride salt of HAL.

[0070] Embodiment 7: A composition for use according to any one of the preceding embodiments, wherein the composition comprises HAL in the range of 0.1 to 5 wt % of the total weight of the composition, or an equivalent concentration of a pharmaceutically acceptable salt of HAL.

[0071] Embodiment 8: The composition for use according to any one of the preceding embodiments, wherein the composition is a semi-solid composition or a liquid composition.

[0072] Embodiment 9: A composition for use according to any one of the preceding embodiments, wherein the composition is a liquid composition comprising a liquid carrier, preferably water, an aqueous solution or an aqueous buffer (preferably a phosphate buffer).

[0073] Embodiment 10: A composition for use according to any of the preceding embodiments, wherein the composition is a liquid composition comprising 5-ALA hexyl hydrochloride at a concentration of 0.2% in an aqueous phosphate buffer, wherein the aqueous phosphate buffer comprises dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0074] Embodiment 11: The composition for use according to any of the preceding embodiments, wherein the composition is instilled into the bladder through a catheter and remains in the bladder for about 20 minutes to about 3 hours.

[0075] Embodiment 12: The composition for use according to any one of the preceding embodiments, wherein at least 1 hour is allowed to elapse from the time the composition is instilled into the bladder to the time the exposure of the interior of the bladder to light is initiated.

[0076] Embodiment 13: The composition for use according to any one of the preceding embodiments, wherein the interior of the bladder is exposed to white light and / or blue light and / or red light.

[0077] Embodiment 14: The composition for use according to embodiment 13, wherein the interior of the bladder is exposed to white light and subsequently to blue light.

[0078] Embodiment 15: The composition for use according to any one of the preceding embodiments, wherein the time between the neoadjuvant therapy and the cystectomy is 0 to 6 weeks.

[0079] Embodiment 16: A composition for use according to any one of the preceding embodiments, wherein the neoadjuvant therapy is performed before, simultaneously with or after other neoadjuvant therapies.

[0080] Embodiment 17: A composition for use according to any of the preceding embodiments, wherein the composition further comprises an anti-PD-L1 antibody and / or an anti-PD-1 antibody.

[0081] Embodiment 18: The composition for use according to embodiment 17, wherein the composition comprises an anti-PD-L1 antibody.

[0082] Embodiment 19: The composition for use according to embodiment 17, wherein the composition comprises an anti-PD-1 antibody.

[0083] Embodiment 20: The composition for use according to embodiment 17, wherein the composition comprises an anti-PD-L1 antibody and an anti-PD-1 antibody.

[0084] Embodiment 21: Neoadjuvant therapy for bladder cancer in a bladder cancer patient scheduled for cystectomy, the therapy comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of the patient and exposing the interior of the bladder to light.

[0085] Embodiment 22: The neoadjuvant therapy according to embodiment 21, wherein the bladder cancer is muscle invasive bladder cancer (MIBC).

[0086] Embodiment 23: The neoadjuvant therapy according to embodiment 21, wherein the bladder cancer is non-muscle invasive bladder cancer (NMIBC).

[0087] Embodiment 24: The neoadjuvant therapy according to embodiment 23, wherein the bladder cancer is NMIBC with a high risk of progression.

[0088] Embodiment 25: The neoadjuvant therapy according to any one of the preceding embodiments, wherein the composition comprises a pharmaceutically acceptable salt of HAL.

[0089] Embodiment 26: The neoadjuvant therapy according to embodiment 25, wherein the composition comprises the hydrochloride salt of HAL.

[0090] Embodiment 27: The neoadjuvant therapy according to any one of the preceding embodiments, wherein the composition comprises HAL in the range of 0.1 to 5 weight % of the total weight of the composition, or an equivalent concentration of a pharmaceutically acceptable salt of HAL.

[0091] Embodiment 28: The neoadjuvant therapy according to any one of the preceding embodiments, wherein the composition is a semisolid composition or a liquid composition.

[0092] Embodiment 29: Neoadjuvant therapy according to any one of the preceding embodiments, wherein the composition is a liquid composition comprising a liquid carrier, preferably water, an aqueous solution or an aqueous buffer, preferably a phosphate buffer.

[0093] Embodiment 30: A neoadjuvant therapy according to any one of the preceding embodiments, wherein the composition is a liquid composition comprising 5-ALA hexyl hydrochloride at a concentration of 0.2% in an aqueous phosphate buffer, wherein the aqueous phosphate buffer comprises dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0094] Embodiment 31: The neoadjuvant therapy according to any one of the preceding embodiments, wherein the composition is instilled into the bladder via a catheter and remains in the bladder for about 20 minutes to about 3 hours.

[0095] Embodiment 32: Neoadjuvant therapy according to any one of the preceding embodiments, wherein at least 1 hour is allowed to elapse from instillation of the composition into the bladder to initiation of exposure of the interior of the bladder to light.

[0096] Embodiment 33: Neoadjuvant therapy according to any one of the preceding embodiments, wherein the interior of the bladder is exposed to white light and / or blue light and / or red light.

[0097] Embodiment 34: The neoadjuvant therapy of Embodiment 33, wherein the interior of the bladder is exposed to white light and subsequently to blue light.

[0098] Embodiment 35: Neoadjuvant therapy according to any one of the preceding embodiments, wherein the time between the neoadjuvant therapy and cystectomy is 0 to 6 weeks.

[0099] Embodiment 36: The neoadjuvant therapy according to any one of the preceding embodiments, wherein the neoadjuvant therapy is performed before, simultaneously with, or after other neoadjuvant therapies.

[0100] Embodiment 37: The neoadjuvant therapy according to any one of the preceding embodiments, wherein the composition further comprises an anti-PD-L1 antibody and / or an anti-PD-1 antibody.

[0101] Embodiment 38: The neoadjuvant therapy according to Embodiment 37, wherein the composition comprises an anti-PD-L1 antibody.

[0102] Embodiment 39: The neoadjuvant therapy according to Embodiment 37, wherein the composition comprises an anti-PD-1 antibody.

[0103] Embodiment 40: The neoadjuvant therapy according to Embodiment 37, wherein the composition comprises an anti-PD-L1 antibody and an anti-PD-1 antibody.

Claims

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

2. The composition for use according to claim 1, wherein The bladder cancer is muscle invasive bladder cancer (MIBC).

3. The composition for use according to claim 1, wherein The bladder cancer is non-muscle invasive bladder cancer (NMIBC).

4. The composition for use according to claim 3, wherein The bladder cancer is NMIBC with a high risk of progression.

5. A composition for use according to any one of the preceding claims, wherein The composition includes a pharmaceutically acceptable salt of HAL.

6. The composition for use according to claim 5, wherein The composition includes the hydrochloride salt of HAL.

7. A composition for use according to any one of the preceding claims, wherein The composition comprises HAL in the range of 0.1 to 5 weight % of the total weight of the composition, or an equivalent concentration of a pharmaceutically acceptable salt of HAL.

8. A composition for use according to any one of the preceding claims, wherein The composition is a semi-solid composition or a liquid composition.

9. A composition for use according to any one of the preceding claims, wherein The composition is a liquid composition comprising a liquid carrier, preferably water, an aqueous solution or an aqueous buffer, preferably a phosphate buffer.

10. A composition for use according to any one of the preceding claims, wherein The composition is a liquid composition comprising 5-ALA hexyl ester hydrochloride at a concentration of 0.2% in an aqueous phosphate buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

11. A composition for use according to any one of the preceding claims, wherein The composition is instilled into the bladder via a catheter and remains in the bladder for about 20 minutes to about 3 hours.

12. A composition for use according to any one of the preceding claims, wherein At least 1 hour is allowed to elapse from the instillation of the composition into the bladder to the start of exposing the interior of the bladder to light.

13. A composition for use according to any one of the preceding claims, wherein The interior of the bladder is exposed to white light and / or blue light and / or red light.

14. The composition for use according to claim 13, wherein The interior of the bladder is exposed to white light and then to blue light.

15. A composition for use according to any one of the preceding claims, wherein The time between the neoadjuvant therapy and the cystectomy was 0 to 6 weeks.

16. A composition for use according to any one of the preceding claims, wherein The neoadjuvant therapy is performed before, simultaneously with, or after other neoadjuvant therapies.

17. A composition for use according to any one of the preceding claims, wherein The composition further comprises an anti-PD-L1 antibody and / or an anti-PD-1 antibody.

18. The composition for use according to claim 17, wherein The composition includes an anti-PD-L1 antibody.

19. The composition for use according to claim 17, wherein The composition includes an anti-PD-1 antibody.

20. The composition for use according to claim 17, wherein The composition includes an anti-PD-L1 antibody and an anti-PD-1 antibody.