Bladder cancer therapy

Abstract

The present invention relates to the treatment of bladder cancer. In particular, the present invention relates to a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of bladder cancer therapy wherein said method comprises instilling said composition into the bladder of a patient, and wherein said method is not a method of photodynamic therapy.

Description

Technical Field

[0001] This invention relates to a treatment for bladder cancer. More particularly, this invention relates to a treatment for bladder cancer in which 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof is instilled into the patient's bladder without photodynamic therapy (PDT).

[0002] This type of therapy can be used as a therapeutic treatment for bladder cancer and as a prophylactic treatment to prevent recurrence of bladder cancer. It can be used as a standalone therapy or as adjuvant or neoadjuvant therapy in combination with other therapies and / or surgical procedures such as radiotherapy, chemotherapy, immunotherapy, transurethral resection (TUR), or radical cystectomy. Background Technology

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

[0004] The diagnosis of bladder cancer ultimately relies on cystoscopy (cystoscopic examination) and histological evaluation of the resected tissue. At 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 is detected during cystoscopy, the patient will undergo transurethral resection (TUR), a procedure that visualizes the bladder through the urethra and removes the tumor and lesion. In the case of non-MIBC, this type of resection aims to completely remove the tumor. In the case of MIBC, this type of resection is palliative. In addition to tumor resection, TUR is performed to achieve a correct histological diagnosis of bladder cancer based on a pathologist's examination of the removed tumor / tumor biopsy.

[0006] For patients with minor malignant cystitis (MIBC), the standard treatment is radical cystectomy, which involves removing the bladder and adjacent organs: the prostate and seminal vesicles in men, and the uterus and adnexa in women. Standard treatment also includes the dissection of local lymph nodes. Cystectomy is also recommended in patients with non-MIBC at high risk of progression, i.e., those with recurrent high-grade tumors, high-grade T1 tumors, or high-grade tumors complicated by carcinoma in situ (CIS). Furthermore, cystectomy is recommended in NMIBC patients who have failed BCG immunotherapy.

[0007] Although radical cystectomy is the gold standard for treating MIBC and is advocated in patients with certain types of NMIBC, it only provides a 5-year survival in about 50% of patients. To improve these unsatisfactory outcomes, the use of neoadjuvant therapy (i.e., therapy prior to cystectomy as the primary treatment) has been explored since the 1980s. Currently, neoadjuvant radiotherapy and neoadjuvant chemotherapy are used.

[0008] For neoadjuvant radiotherapy, downstaging of the cancer following radiotherapy takes approximately 4–6 weeks. However, surgical delays exceeding 90 days have been shown to cause a significant increase in extravesical disease in patients with locally advanced bladder cancer (81% vs. 52%). According to current European guidelines for MIBC, neoadjuvant radiotherapy is not recommended because there is no data to support an increase in survival for operable MIBC.

[0009] Neoadjuvant chemotherapy has several advantages, including delivery at the earliest possible time point when the burden of micrometastatic disease is expected to be low; better tolerability of chemotherapy is expected before cystectomy than after; and hypothetically, patients with micrometastatic disease may respond to neoadjuvant therapy and exhibit favorable pathological conditions primarily determined by negative lymph node status and negative surgical margins. Neoadjuvant chemotherapy containing cisplatin has been shown to significantly improve survival (an absolute improvement of 5% in survival at 5 years). However, as noted above, delayed cystectomy may impair outcomes in patients insensitive to chemotherapy, and preoperative anemia and neuropathy are generally more common in patients who receive neoadjuvant chemotherapy prior to cystectomy. Current European guidelines on MIBC state that "...neoadjuvant chemotherapy has limitations regarding patient selection, current surgical techniques, and current combinations of chemotherapy." Therefore, there is room for improvement in neoadjuvant therapy for bladder cancer patients who are scheduled for cystectomy, i.e., those diagnosed with MIBC or NMIBC at high risk of progression, including high-grade tumors with multiple recurrences or high-grade T1 tumors or high-grade tumors with concurrent carcinoma in situ (CIS).

[0010] For patients with non-MIBC, the standard treatment is tumor resection via transurethral resection (TUR). Instilling a composition containing HAL or a pharmaceutically acceptable salt thereof into the bladder and exposing the bladder interior to blue light can improve visualization of bladder cancer during cystoscopy and / or TUR. As a standard procedure, cystoscopy and TUR are performed using white light. However, because the use of white light can lead to missed lesions that are present but not visible, photodynamic diagnosis / detection (PDD) is often used in such procedures. Generally, PDD involves applying a photosensitizer or its precursor (collectively referred to herein as a “photosensitizer”) to the region of interest. The photosensitizer or its precursor is taken up into the cells, where the precursor is converted into the photosensitizer. When the region of interest is exposed to light of an appropriate wavelength, the photosensitizer is activated (i.e., excited), and upon relaxation to its ground state, fluorescence occurs and is detected.

[0011] 5-ALA hexyl ester (hexaaminolevulinate, HAL) and its salts are known photosensitizer precursors. HAL preferably penetrates rapidly proliferating cells, such as tumor cells, where it is converted into porphyrins (e.g., protoporphyrin IX, "PpIX"), which are photosensitizers. Upon activation with blue light, the porphyrin is activated and, upon relaxing to its ground state, emits red light, thus enabling specific and accurate visualization of tumors. In the United States and Canada as Sales Photocure ASA (Norway) is a commercially available, approved drug containing HAL and used for PDD in cystoscopy and TUR procedures.

[0012] In patients with non-malignant cystoscopic brain cancer (NMIBC), HAL-guided cystoscopy and transurethral resection (TUR) enhance the detection of papillary tumors and carcinoma in situ (CIS) lesions, which are difficult to detect with white light alone. Compared with white light TUR alone, HAL-guided TUR for bladder cancer in NMIBC patients further reduces residual tumor rates after such procedures and produces excellent recurrence-free survival (RFS) rates and prolonged RFS intervals (see Rink M et al., Eur Urol 4(64), 2013, 624). Existing European guidelines and several expert consensus statements on NMIBC recommend the use of HAL-guided TUR in various settings for the management of NMIBC, and some even recommend HAL-guided TUR at the initial TUR in all NMIBC patients (see Witjes JA et al., Eur Urol 1(66), 2014, 863).

[0013] Although TaT1 tumors can be completely removed by HAL-guided transurethral resection (TUR), and HAL-guided TUR has a beneficial effect on recurrence rates, in a limited number of cases, these tumors recur and progress to muscle-invasive bladder cancer. Therefore, it is necessary to consider adjuvant therapy in all patients, i.e., adjuvant chemotherapy or adjuvant chemotherapy and adjuvant immunotherapy. The choice of therapy can be considered differently depending on the individual patient's acceptable risk. Typically, patients will receive a single, immediate, TUR-following infusion of chemotherapy into the bladder. The need for further adjuvant intravesical therapy depends on the patient's prognosis. In patients with a low risk of tumor recurrence, a single, immediate infusion reduces the risk of recurrence and is considered standard treatment, i.e., no further treatment is given in these patients before recurrence. However, for other patients, a single, immediate infusion remains incomplete treatment because the likelihood of recurrence and / or progression is quite high. No single chemotherapy drug is superior in terms of efficacy; mitomycin C, epirubicin, and doxorubicin have all shown beneficial effects. However, mitomycin C (MMC) is often the drug of choice.

[0014] According to the EAU guidelines for the treatment of non-MIBC, in patients with TaT1 tumors at intermediate or high risk of recurrence and intermediate or high risk of progression, at least one year of BCG immunotherapy should be administered following a single infusion of chemotherapy, or further infusions of chemotherapy. In patients with bladder CIS, at least one year of intravesical BCG is indicated.

[0015] Assuming maintenance therapy with BCG is necessary for optimal efficacy, the issue of BCG toxicity becomes even more relevant. Due to the more significant side effects of BCG compared to intravesical chemotherapy, its use remains reluctant. Deaths due to BCG sepsis and frequent BCG-induced cystitis and anaphylactic reactions have already hampered its applicability. Furthermore, treatment failure with BCG is not uncommon.

[0016] Photodynamic therapy (PDT) has also been suggested for the treatment of bladder cancer, and clinical studies have been conducted to investigate the efficacy and safety of this treatment. Similar to photodynamic therapy (PDD), PDT involves applying a photosensitizer to the region of interest, followed by activation of the photosensitizer with light of a wavelength suitable for inducing the PDT effect (i.e., photoactivated light). The therapeutic effect of PDT is based on a phototoxic reaction: the photosensitizer is taken into cells, where, if the agent is a precursor to the photosensitizer, the precursor is converted into the photosensitizer. When the region of interest is exposed to photoactivated light, the photosensitizer is activated, i.e., excited from the ground singlet state to the excited singlet state. The photosensitizer then undergoes intersystem crossing to become the longer-lived excited triplet state. One of the few chemicals present in tissues with a ground triplet state is molecular oxygen. When an activated photosensitizer and an oxygen molecule come into contact, energy transfer can occur, allowing the activated photosensitizer to relax to its ground singlet state and produce an excited singlet oxygen molecule. Singlet oxygen is a highly corrosive chemical and will react rapidly with any nearby biomolecules. Ultimately, these reactions will kill cells, namely cancer cells.

[0017] HAL and its salts have been suggested for use in phototherapy (PDT) for bladder cancer (see, for example, US2005 / 0031541, Example 21). Use of HAL and its salts in bladder cancer PDT, wherein HAL is instilled into the patient's bladder and the bladder interior is exposed to blue light, has also been proposed (see WO 2017 / 103285 and US 2019 / 0022404); in neoadjuvant therapy for bladder cancer in patients scheduled for cystectomy, wherein HAL is instilled into the patient's bladder and the bladder interior is exposed to light (WO 2017 / 103283 and US2018 / 0369379); and in bladder cancer therapy, wherein a combination of HAL and anti-PD-L1 and / or anti-PD-1 antibodies is instilled into the bladder and the bladder interior is exposed to light (WO 2017 / 103280). Bader et al., Urol. Oncol. Seminars and Original Investigations 31, 2013, 1178-1183, have performed HAL PDT using HAL solutions (8 mM and 16 mM). Irradiation was performed with white light from a xenon lamp, and the light was delivered into the bladder via a glass fiber inserted into the working channel of the cystoscope. Photoactivated light was employed in all these early PDT methods using HAL and its salts.

[0018] Some of the disadvantages of the aforementioned PDT methods are that they require specially designed equipment that is not commercially available. Furthermore, the use of optical fibers and the placement of the fiber tip in the center of the bladder are complex and cumbersome. The position of the fiber tip needs to be verified by ultrasound, or the PDT procedure may need to be interrupted to ensure that the fiber tip remains centered and does not contact the bladder wall, which could cause damage. In addition, side effects frequently occur and, depending on the PDT parameters used, may take a long time to subside.

[0019] Therefore, alternative (e.g., improved) methods for managing bladder cancer are still needed.

[0020] As discussed in Saleh Al-Omari, Biophys. Rev. (2013) 5:305-311, researchers have reported the dark toxicity of certain photosensitizers in cell lines. Dark toxicity refers to the cytotoxicity of photosensitizers on cancer cells in the absence of light. The studies described by Saleh Al-Omari in that article did not involve HAL (or 5-ALA or 5-ALA derivatives), and all studies investigated dark toxicity in cell cultures.

[0021] In Example 21 of US2015 / 0191419, the dark toxicity of HAL was determined in WiDr cells derived from primary adenocarcinoma of the rectum and sigmoid colon. HAL was added to the cell culture medium at concentrations from 0.001 mM to 1 mM. Weak cytotoxicity was observed in the range of 0.3 mM to 1 mM, with a minimum cell viability of 85%, meaning that only 15% or less were killed.

[0022] Neither Saleh Al-Omari nor US2015 / 0191419 reported any investigations into the dark toxicity of HAL in bladder cancer cell lines. Studies in in vitro cell lines, i.e., on isolated tumor cells, differ from the real-world situation in patients (e.g., in bladder cancer patients), where the tumor is surrounded by a tumor microenvironment that can affect the efficacy of any treatment. Therefore, known dark toxicity studies have not revealed any dark toxicity of HAL or its salts to patient bladder tumors.

[0023] US2013 / 0158293 relates to enhancers for use in cancer hyperthermia, which contain 5-ALA and 5-ALA derivatives. Hyperthermia is a treatment method that utilizes the fact that cancer cells are more sensitive to heat than normal cells, thereby inhibiting the proliferation of cancer cells. At a temperature of 42°C (i.e., above body temperature), 5-ALA has shown anti-cancer effects in various cell lines in the absence of photodynamic therapy (i.e., without light). However, no results are provided regarding HAL or any of its salts (or any other 5-ALA derivatives, such as 5-ALA esters). Furthermore, the document does not mention any potential treatment for bladder cancer. Summary of the Invention

[0024] As demonstrated herein, the applicant has now surprisingly discovered that intravesical (i.e., endovesical) administration of 5-ALA hexyl ester (HAL) effectively eradicates tumors in the bladder or reduces tumor proliferation in the absence of photodynamic therapy, i.e., in the absence of photoactivated light. As a result of this discovery, the applicant proposes that HAL or a pharmaceutically acceptable salt thereof be used as a therapy for treating bladder cancer or reducing its recurrence, without the combination with photoactivated light. While not wishing to be bound by theory, it is assumed that the therapy according to the invention effectively stimulates the patient's immune system, thereby not only combating bladder cancer but also reducing its recurrence rate after treatment.

[0025] The therapies described in this article can be combined with other treatments for bladder cancer, including surgery, chemotherapy, and / or immunotherapy. Therefore, the use of the therapies described in this article as adjuvant or neoadjuvant therapy in the management of bladder cancer is also proposed.

[0026] Because this therapy is performed in the absence of light-activated light, it addresses issues associated with conventional PDT methods, where light delivery within the patient's bladder can be complex and cumbersome, requiring specially designed equipment. Furthermore, the use of HAL or its pharmaceutically acceptable salts in the absence of light-activated light is expected to be well-tolerated by patients with minimal side effects.

[0027] In one aspect, the present invention therefore provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, the composition for use in a method of bladder cancer therapy, wherein the method comprises instilling the composition into a patient's bladder, and wherein the method is not a method of photodynamic therapy.

[0028] In another aspect, the present invention provides a method for treating bladder cancer, the method comprising the step of instilling a composition containing 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into a patient's bladder, and wherein said method is not a method of photodynamic therapy. Detailed Implementation

[0029] definition

[0030] As used herein, the term “photodynamic therapy” or “PDT” refers to a treatment involving the combined use of (i) a photosensitizer; and (ii) photoactivating light, i.e., light having an appropriate wavelength to activate the photosensitizer and convert it into a therapeutically active form. A photosensitizer may be a photosensitizer or a precursor of a photosensitizer. In some cases, the photosensitizer is a precursor of a photosensitizer that can be administered to the patient and converted into a photosensitizer in vivo. 5-ALA hexyl ester (HAL) is an example of a precursor to the photosensitizer protoporphyrin IX (“PpIX”). PDT involves applying a photosensitizer to a treatment area and then exposing the treatment area to photoactivating light. The photosensitizer is therapeutically inactive prior to exposure to the photoactivating light. Only after exposure to the photoactivating light (i.e., “photoactivation”) does the photosensitizer convert into a therapeutically active form. Light capable of activating a photosensitizer and converting it into a therapeutically active form (i.e., “photoactivating light”) is therefore a fundamental component of any photodynamic therapy approach. As will be understood, the properties of the photoactivating light will vary depending on the photosensitizer. In order to achieve the desired photoactivation and thus the expected therapeutic effect, light must be delivered at a certain dose (i.e., light dose) and at a suitable, defined wavelength and flux rate.

[0031] As used herein, the term "cancer" refers to cells that undergo abnormal proliferation. The growth of such cells typically leads to the formation of a tumor. As used herein, the term "tumor" refers to an abnormal mass of tissue containing cancerous cells. Cancerous cells can be benign, pre-malignant, or malignant. Such cells can be invasive and / or have the ability to metastasize to other sites in the body. As used herein, the term cancer includes cancerous growth, tumors, and metastasis.

[0032] As used in this article, the term "metastasis" refers to the spread of malignant tumor cells from one organ or part of the body to another non-adjacent organ or part of the body. Cancer cells can detach from the primary tumor, enter the lymphatic and blood systems, and circulate to other parts of the body (e.g., normal tissues). Here they can settle and grow within normal tissues. When tumor cells metastasize, the new tumor can be called metastatic cancer.

[0033] As used in this article, the term "bladder cancer" refers to cancer originating from the bladder tissue. Bladder cancer is classified according to the extent of cancer spread (i.e., staging) and graded based on the abnormalities and invasiveness of the cells as observed under a microscope. Staging is usually performed by transurethral resection of the bladder tumor (TUR) and radiological imaging (e.g., CT or MRI). Papillary tumors confined to the mucosa or invading the lamina propria are classified as Ta or T1. Flat lesions of the basement membrane that do not invade the bladder mucosa are called Tis (in situ). For therapeutic purposes, all three categories (Tis, Ta, and T1) are grouped together as non-muscle-invasive disease, i.e., non-muscle-invasive bladder cancer (NMIBC). Tumors in the remaining categories (T2, T3, and T4) are called muscle-invasive disease, i.e., muscle-invasive bladder cancer (MIBC).

[0034] As used herein, “treatment” means the reduction, alleviation, or elimination of a disease. Treatment includes palliative care, which aims to minimize, partially suppress, or completely suppress the development of the disease. In the context of this invention, the disease is bladder cancer.

[0035] As used in this article, “prevention” means absolute prevention, that is, maintaining a normal level with respect to the degree or occurrence of a particular symptom of the disease, or reducing or alleviating the degree or duration of the symptom (e.g., delaying its occurrence).

[0036] "Pharmaceutical composition" means any composition in any form suitable for medical purposes.

[0037] As used herein, "therapeutic effective amount" refers to the amount that will produce the desired therapeutic effect, i.e., the amount of a drug that is effective in achieving its intended purpose for treatment or prevention. Such an amount can be provided by a single administration or by multiple (e.g., repeated) administrations of any drug described herein. For example, it may be necessary to administer several doses of the drug described herein to constitute a "therapeutic effective amount" that will produce the desired therapeutic effect. While the needs of an individual patient may vary, determining the optimal range of effective amounts of the drugs described herein is within the capabilities of those skilled in the art. Generally, those skilled in the art can select a dosage regimen for treating a disease with any drug described herein based on a variety of factors, including the degree and severity of the disease.

[0038] As used in this article, the term "patient" refers to a human subject in a clinical setting.

[0039] As used herein, the term “5-ALA hexyl ester” (HAL) refers to hexyl aminolevulinic acid ester, namely hexyl 5-amino-4-oxo-valerate.

[0040] As used herein, the term “pharmaceuticalally acceptable salt” means a salt that is suitable for and meets requirements related to, for example, safety, bioavailability and tolerability (see, for example, PHStahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002).

[0041] As used in this article, the term "adjunctive therapy" refers to the application of therapeutic or preventative agents in addition to the primary treatment of a disease.

[0042] As used in this article, the term “neoadjuvant therapy” refers to the administration of a therapeutic or preventative agent prior to (i.e., before) the primary treatment of a disease.

[0043] The bladder cancer treatment according to the invention is not a photodynamic therapy, i.e., it does not rely on the activation of a photosensitizer by photoactivated light. It is alternatively referred to as "non-photodynamic." Unlike known methods involving the use of HAL or its salts in the treatment of bladder cancer, the therapy described herein relies on the action of HAL or its pharmaceutically acceptable salts in the absence of photoactivated light. This therapy does not involve delivering photoactivated light into the patient's bladder after administration of HAL or one of its pharmaceutically acceptable salts intrabladder (i.e., inside the bladder).

[0044] The compositions used in this invention can inhibit or delay tumor growth and / or prevent tumor recurrence in a patient's bladder without requiring photodynamic therapy to achieve this therapeutic effect. Specifically, the compositions are used in methods that do not involve the use of light-activated light from a photosensitizer, PpIX, capable of producing a therapeutically active form in vivo.

[0045] The light wavelengths generally considered suitable for producing a therapeutically active form of the photosensitizer PpIX in vivo after administration of HAL or its pharmaceutically acceptable salts include: white light, i.e., visible light with wavelengths from about 350 nm to about 700 nm; blue light, i.e., light with wavelengths from about 360 nm to about 450 nm; and red light, i.e., light with wavelengths from about 600 nm to about 670 nm. The method of the therapy according to the invention is performed without exposing the interior of the patient's bladder to white light, blue light, or red light, or any combination thereof, wherein two or more wavelengths of light are used simultaneously (i.e., at the same time) or sequentially (i.e., successively). The light dose administered during PDT, while irradiating the interior of the bladder with white light and / or red light and / or blue light, can vary. Typically, these can be around 0.01 J / cm². 2 Up to 100J / cm 2Within a certain range. The infusion rate used during PDT (phototherapy) to irradiate the interior of the bladder with white and / or red and / or blue light can vary. In a standard PDT approach, the duration of light exposure will vary. Typically, light can be provided for periods ranging from approximately 10 to 30 minutes.

[0046] In some embodiments, the bladder cancer treatment according to the invention is performed without the application of heat; that is, it is not a method of thermotherapy in which the patient's bladder is subjected to heating. In one embodiment, the treatment is performed at body temperature, for example, at a temperature in the range of about 35°C to about 38°C, or, for example, about 36°C to about 37°C.

[0047] The composition comprising HAL or a pharmaceutically acceptable salt thereof, used in this invention, is instilled into the patient's bladder, preferably via a catheter. Preferably, the composition is retained in the bladder for a predetermined time period. The patient's bladder is preferably empty at the time of instillation, and may be emptied prior to instillation if necessary.

[0048] Once instilled into the patient's bladder, the composition can remain in the bladder for a predetermined time period. The appropriate time period can be readily determined by those skilled in the art. The composition can remain in the bladder for, for example, from about 10 minutes to about 3 hours, preferably from about 20 minutes to about 2 hours, and more preferably from about 30 minutes to 1 hour. Advantageously, the composition can remain in the patient's bladder for at least about 30 minutes or at least about 1 hour. At the end of this period, the bladder is emptied. If the patient cannot retain the composition for the appropriate time period, such as about 10 minutes, or about 20 minutes, or about 30 minutes, or about 1 hour, the instillation procedure can be repeated.

[0049] In one embodiment, the composition is instilled into the patient's bladder via a catheter and remains in the bladder for approximately 30 minutes or approximately 1 hour. The bladder is then emptied.

[0050] The compositions used in this invention comprise 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof. The synthesis of 5-ALA hexyl ester is known in the art. It can be prepared, for example, as described in WO 96 / 28412, the entire contents of which are incorporated herein by reference. For example, 5-ALA hexyl ester can be prepared by reacting 5-ALA with hexanol in the presence of a catalyst (such as an acid). Alternatively, 5-ALA hexyl ester hydrochloride is commercially available, for example, in [specific form missing]. (e.g., available from Photocure ASA) or (For example, available from Photocure Inc.)

[0051] 5-ALA hexyl ester used in this invention can be employed in the form of a pharmaceutically acceptable salt. Such salts are preferably acid addition salts of a pharmaceutically acceptable organic or inorganic acid. Suitable acids include, for example, hydrochloric acid, nitric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfonic acid, and sulfonic acid derivatives. Such salts of ALA esters are described in WO 2005 / 092838, the entire contents of which are incorporated herein by reference. The preferred acid addition salt of HAL used in this invention is a hydrochloride salt. The synthetic procedures for forming the salt are conventional in the art and are described, for example, in WO 2005 / 092838.

[0052] The composition will contain a therapeutically effective amount of HAL or a pharmaceutically acceptable salt. An appropriate concentration can be readily determined by those skilled in the art. Conveniently, the concentration is in the range of 0.1% to 5% by weight of the total composition, or an equivalent concentration of a pharmaceutically acceptable salt of HAL, preferably 0.15% to 3.5%, most preferably 0.17%, corresponding to, for example, 0.2% HAL hydrochloride (8 mM).

[0053] The compositions used in this invention are pharmaceutical compositions and may contain pharmaceutically acceptable carriers or excipients, such as stabilizers. The compositions are preferably liquid compositions, more preferably suspensions, or even more preferably solutions of HAL in a liquid carrier. Preferred liquid carriers include water and aqueous solutions, such as aqueous buffer solutions.

[0054] In one embodiment, the composition used in this invention is an aqueous solution of HAL or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the composition used in the present invention is a solution of HAL or a pharmaceutically acceptable salt thereof in an aqueous buffer such as an aqueous phosphate buffer. In one embodiment, the composition used in the present invention comprises an aqueous phosphate buffer containing disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide, and water.

[0056] In one embodiment, the composition used in this invention is an aqueous solution of HAL hydrochloride. For example, the composition may be a solution of HAL hydrochloride in an aqueous buffer solution.

[0057] If the composition used in this invention is a liquid composition containing water, the pH of the composition is preferably in the range of 4.5 to 7.5, more preferably in the range of 5.7 to 7.2.

[0058] In one embodiment, HAL or a pharmaceutically acceptable salt thereof is provided in lyophilized form and reconstituted in a liquid carrier, preferably in water or an aqueous solution, and most preferably in an aqueous buffer solution prior to use.

[0059] In one embodiment, the composition used in this invention is That is, a solution of HAL hydrochloride (2 mg / ml; 8 mM) in an aqueous buffer solution containing disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0060] The amount of composition to be infused into the patient's bladder can vary depending on the patient's bladder volume. A suitable amount can be readily determined by those skilled in the art. Generally, a volume of about 50 ml of the composition may be suitable. For example, a volume of about 50 ml of a composition containing 0.2% HAL hydrochloride (8 mM) is suitable and sufficient. Using a volume of about 50 ml... It is considered appropriate.

[0061] In one embodiment, the composition for instillation into the patient's bladder is a solution containing 2 mg / ml HAL hydrochloride.

[0062] In one embodiment, the composition used in the present invention may further comprise an anti-PD-L1 antibody and / or an anti-PD-1 antibody. Anti-PD-L1 is a monoclonal antibody designed to interfere with a protein called PD-L1 (programmed death ligand 1). Anti-PD-L1 targets PD-L1 expressed on cancer cells and tumor-infiltrating immune cells, preventing its binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, anti-PD-L1 can achieve T cell activation, restoring its ability to effectively detect and attack bladder cancer cells. Anti-PD-1 is a monoclonal antibody that binds to the PD-1 (programmed death receptor-1) protein, which is present at high levels in many cancer types, such as bladder cancer. By competitively blocking interaction with the PD-1 receptor, anti-PD-1 is believed to thereby restore anti-cancer T cell responses. Therefore, anti-PD-L1 antibodies and anti-PD-1 antibodies target different components of the same interaction mechanism between immune cells (especially cytotoxic T cells) and cancer cells, but have similar therapeutic effects: anti-PD-L1 antibodies target PD-L1 expressed on cancer cells, while anti-PD-1 antibodies target the other half of this mechanism, PD-1, expressed on cytotoxic T cells. As will be understood, the anti-PD-L1 antibodies and anti-PD-1 antibodies mentioned in this article are used to inhibit PD-L1 and PD-1, respectively. Therefore, these can also be referred to as antagonistic anti-PD-L1 antibodies and antagonistic anti-PD-1 antibodies.

[0063] Therefore, in another aspect, the present invention provides a composition for use in a method of treating bladder cancer, wherein the composition comprises: (i) 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof; and (ii) an anti-PD-L1 antibody and / or an anti-PD-1 antibody, and the method comprises instilling the composition into the bladder of a patient, and further wherein the method is not a method of photodynamic therapy.

[0064] In another aspect, the present invention provides a method of bladder cancer therapy comprising the step of instilling a composition into a patient’s bladder, the composition comprising: (i) 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof; and (ii) an anti-PD-L1 antibody and / or an anti-PD-1 antibody, wherein the method is not a method of photodynamic therapy.

[0065] Preferred anti-PD-L1 antibodies for use in this invention are those from Roche, particularly MPDL3280A. Such 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.

[0066] Preferred anti-PD-1 antibodies for use in this invention are those from Merck, particularly pembrolizumab (Keytruda). Such 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.

[0067] Other preferred anti-PD-1 antibodies that can be used in this invention are those from Bristol-Myers Squibb, preferably nivolumab (Opdivo). Such anti-PD-1 antibodies are described in WO 2004 / 004771, the entire contents of which are incorporated herein by reference.

[0068] When the compositions used in this invention further comprise anti-PD-L1 antibodies and / or anti-PD-1 antibodies, these will be present in therapeutically effective amounts. The precise amount will depend on various factors, such as the selected anti-PD-L1 and / or anti-PD-1 antibodies, whether the therapy is intended for the treatment and / or prevention of bladder cancer, whether the therapy is a standalone therapy or intended as adjuvant or neoadjuvant therapy in combination with other therapies and / or surgical procedures (such as those described herein), etc. Those skilled in the art can readily determine the therapeutically effective amount of anti-PD-L1 and / or anti-PD-1 antibodies by considering such factors.

[0069] The method of bladder cancer therapy according to the present invention can be used to treat bladder cancer. For use in such treatment, the composition is administered to a patient in need, i.e., a patient diagnosed with bladder cancer.

[0070] Bladder cancer can be either non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC).

[0071] In one implementation, bladder cancer is MIBC, where the cancer has spread to the muscular layer of the bladder.

[0072] In one implementation, bladder cancer is non-malignant bladder cancer (NMIBC), where the cancer has not yet penetrated the muscular layer of the bladder. This type of cancer presents as papillary tumors and flat lesions (carcinoma in situ, CIS).

[0073] In one implementation, bladder cancer is NMIBC with a high risk of progression, such as high-grade tumors with multiple recurrences, high-grade T1 tumors, or high-grade tumors with concurrent carcinoma in situ (CIS).

[0074] For use in the treatment of bladder cancer, the therapy according to the invention can be administered once or repeatedly, depending on the extent and invasiveness of the cancer. For example, it can be administered two or more times, such as 3, 4, 5, 6, 7, 8, 9, or 10 times, with a certain interval between treatments. In some cases, it can be administered more than 10 times. The interval between treatments can vary, but can be, for example, in the range of about 4 days to 4 weeks, for example, 1 week, 2 weeks, or 3 weeks. In some embodiments, the therapy according to the invention is repeated in the form of induction therapy followed by maintenance therapy. In some embodiments, induction therapy includes administering the therapy according to the invention two or more times, such as 3, 4, 5, 6, 7, 8, 9, or 10 times, for example, 5, 6, 7, or 8 times, with an interval of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days between treatments, such as 6, 7, 8, 9, or 10 days. For example, induction therapy can include administering the therapy according to the invention once a week for a period of about 6 weeks. In some implementations, maintenance therapy includes administering the therapy according to the invention once a week for a period of two, three, or four weeks. Such maintenance therapy may be administered once, twice, three times, or four times a year.

[0075] The method of bladder cancer treatment according to the present invention can be used as a standalone treatment for bladder cancer. Preferably, it can be used as an adjunct therapy in the treatment of bladder cancer, i.e., in addition to the primary (i.e., main) therapy for bladder cancer.

[0076] In another embodiment, the present invention therefore provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, the composition being used in a method of adjuvant therapy for bladder cancer, wherein the method comprises instilling the composition into the bladder of a patient, and wherein the method is not a method of photodynamic therapy.

[0077] In another embodiment, the present invention provides a method of adjuvant therapy for bladder cancer, the method comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient, and wherein said method is not a method of photodynamic therapy.

[0078] The adjuvant therapy according to the invention can be administered before, simultaneously with, or after the primary treatment of the disease (i.e., bladder cancer). The primary treatment for bladder cancer will depend on the patient's diagnosis, such as whether they have been diagnosed with NMIBC or MIBC.

[0079] For NMIBC patients, such as those with TaT1 tumors of low risk of recurrence and progression, or TaT1 tumors or CIS of intermediate or high risk of recurrence and intermediate risk of progression, the primary treatment is usually transurethral resection (TUR), a surgical procedure in which a cystoscope is used to visualize the interior of the bladder through the urethra to detect and identify tumors and lesions and to remove them. The adjuvant therapy according to the invention can be performed before or after TUR, or both.

[0080] In one embodiment, the present invention therefore provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of adjuvant therapy for bladder cancer, wherein the method comprises instilling the composition into the bladder of a bladder cancer patient, wherein the patient has undergone TUR and / or will undergo TUR, and wherein the method is not a method of photodynamic therapy.

[0081] In another embodiment, the present invention provides a method of adjuvant therapy for bladder cancer in patients who have undergone TUR and / or will undergo TUR, the method comprising instilling a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of the patient, wherein the method is not a method of photodynamic therapy.

[0082] In one embodiment, the method of the therapy of the present invention is performed as an adjunct therapy to TUR in patients who require such treatment, i.e., patients diagnosed with or suspected of having NMIBC.

[0083] In one embodiment, the adjunctive therapy of the present invention may be performed after a transurethral resection of the body (TUR). When performed after a TUR, the adjunctive therapy for treating non-MIBC will include instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient who has undergone a TUR. In one embodiment, the adjunctive therapy of the present invention is performed directly after a TUR. In another embodiment, the adjunctive therapy of the present invention is performed as a separate procedure after a TUR, for example, days, weeks, or months after the TUR procedure. For example, the adjunctive therapy of the present invention may be performed 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or longer, or 1, 2, 3, 4, or 5 weeks or longer, or 1, 2, 3, 4, 5, or 6 months later.

[0084] In another embodiment, the adjunctive therapy of the present invention may be performed prior to TUR. When performed prior to TUR, the adjunctive therapy for treating patients suspected of having NMIBC will include instilling a composition containing 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of such patients. In one embodiment, the adjunctive therapy of the present invention is performed directly prior to TUR. In another embodiment, the adjunctive therapy of the present invention is performed as a separate procedure prior to TUR, for example, days, weeks, or months before the TUR procedure. For example, the adjunctive therapy of the present invention may be performed 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or longer, or 1, 2, 3, 4, or 5 weeks or longer, or 1, 2, 3, 4, 5, or 6 months prior to TUR.

[0085] Any routine transurethral resection (TUR) procedure used to treat non-MIBC or suspected NMIBC can be used as the primary treatment. Such procedures may involve photodynamic detection of lesions in the bladder, for example, using HAL or a pharmaceutically acceptable salt thereof with blue light. TUR procedures typically involve using a cystoscope and exposing the patient's bladder interior to white light from the cystoscope for visual examination to detect and identify lesions, followed by removal of the lesion. In some cases, TUR procedures may involve photodynamic detection (PDD) of the lesion. If TUR procedures involve photodynamic detection of the lesion, the TUR procedure may include: a) instilling a composition containing 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder; b) exposing the interior of the bladder to white light for visual examination, followed by exposing the interior of the bladder to blue light for fluorescence detection of the lesion; c) exposing the bladder to white light to remove the lesion; and d) optionally monitoring the completeness of removal by re-exposing the interior of the bladder to blue light for fluorescence detection of residual lesions.

[0086] In one embodiment, the present invention therefore provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating NMIBC by performing transurethral resection of NMIBC followed by adjunctive therapy comprising instilling the composition into the bladder, wherein the adjunctive therapy is not a method of photodynamic therapy.

[0087] In another embodiment, the present invention provides a method for treating NMIBC in a patient in need, the method comprising performing transurethral resection of the NMIBC and subsequently adjuvant therapy comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder, wherein the adjuvant therapy is not a method of photodynamic therapy.

[0088] In another embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating a patient suspected of having NMIBC, the method comprising performing an adjunctive therapy comprising instilling the composition into the patient's bladder, wherein the adjunctive therapy is not a photodynamic therapy method, and followed by transurethral resection of NMIBC.

[0089] In another embodiment, the present invention provides a method for treating a patient suspected of having NMIBC, the method comprising performing adjunctive therapy comprising instilling a composition containing 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder, wherein the adjunctive therapy is not a method of photodynamic therapy, and followed by transurethral resection of NMIBC.

[0090] In another embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient suspected of having NMIBC or diagnosed with NMIBC, the method comprising: a) performing adjunctive therapy comprising instilling the composition into the patient's bladder, wherein the adjunctive therapy is not a photodynamic therapy; b) subsequently performing transurethral resection of NMIBC; and c) subsequently performing further adjunctive therapy according to step a).

[0091] In another embodiment, the present invention provides a method for treating a patient suspected of having NMIBC or diagnosed with NMIBC, the method comprising: a) administering adjuvant therapy comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of the patient, wherein the adjuvant therapy is not a method of photodynamic therapy; b) performing transurethral resection of NMIBC; and c) subsequently administering further adjuvant therapy according to step a).

[0092] The adjunctive therapy for NMIBC or suspected NMIBC according to the present invention can be performed once or repeatedly. For example, it can be performed two or more times, such as 3, 4, 5, 6, 7, 8, 9 or 10 times, or more than 10 times, wherein the cycle between each treatment is several days or several weeks, such as 4 days to 4 weeks, or 1, 2 or 3 weeks.

[0093] The therapy according to the invention can optionally be used as adjuvant therapy in the treatment of bladder cancer, in combination with radiotherapy, chemotherapy and / or immunotherapy.

[0094] In one embodiment, the therapy of the present invention for treating NMIBC can be used in combination with chemotherapy, such as systemic or intravesical administration of a chemotherapy agent suitable for NMIBC, such as cisplatin, methotrexate, vinblastine, valrubicin, doxorubicin, or mitomycin C, and / or in combination with an immunotherapy agent suitable for NMIBC, such as systemic administration of an anticancer vaccine or intravesical administration of BCG.

[0095] Alternatively, the adjuvant therapy for treating NMIBC according to the invention can replace or partially replace other adjuvant therapies, such as chemotherapy and / or immunotherapy. In one embodiment, the adjuvant therapy according to the invention replaces or partially replaces other adjuvant therapies administered intravesically, such as mitomycin C and / or BCG. In one embodiment, the adjuvant therapy for treating NMIBC according to the invention partially or completely replaces BCG. BCG treatment is typically initiated several weeks after transurethral resection of NMIBC and administered weekly for 6 weeks, optionally followed by a maintenance period in which BCG is administered weekly for three weeks, for example at the three-month, six-month, and 12-month markers. The adjuvant therapy according to the invention can replace 1, 2, 3, 4, 5, or all 6 such BCG treatments and / or maintenance BCG treatments.

[0096] Up to 40% of patients with non-malignant bladder cancer (NMIBC) will fail intravesical BCG therapy. The vast majority of low-grade NMIBC is prone to recurrence but rarely progresses. Failure after intravesical BCG in these patients is usually superficial and low-grade, and such patients can be managed with intravesical protocols, including repeated BCG, BCG plus cytokines, intravesical chemotherapy, hyperthermic chemotherapy, or novel immunotherapies. At the other end of this range, failure to respond to BCG in high-risk T1 bladder cancer and / or carcinoma in situ is more problematic because those tumors often have the potential to progress to muscle invasion. In these cases, radical cystectomy remains the primary treatment option after BCG failure. Complete replacement of BCG with adjuvant therapy according to the invention can be used in patients with BCG-refractory NMIBC, i.e., patients for whom BCG therapy fails to produce the expected treatment success.

[0097] In one embodiment, the present invention therefore provides an adjunctive therapy for treating NMIBC in patients with BCG refractory, the adjunctive therapy comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of the patient with BCG refractory, wherein said adjunctive therapy is not a method of photodynamic therapy.

[0098] For patients with MIBC, the primary treatment is radical cystectomy, which involves removing the bladder and, if applicable, adjacent organs, namely the prostate and seminal vesicles in men, and the uterus and adnexa in women, including dissection of local lymph nodes. Cystectomy is also recommended in patients with NMIBC at high risk of progression, namely those with recurrent high-grade tumors, high-grade T1 tumors, or high-grade tumors with concurrent carcinoma in situ (CIS). Furthermore, cystectomy is recommended in NMIBC patients who have failed BCG immunotherapy. For patients scheduled for cystectomy, the therapy according to the invention can be administered as neoadjuvant therapy, i.e., prior to cystectomy as the primary treatment.

[0099] In one embodiment, the therapy of the present invention is therefore a neoadjuvant therapy for bladder cancer patients scheduled for cystectomy. Such patients are those for whom a physician has decided to perform a cystectomy, i.e., the patient will undergo surgery to remove the bladder within a predetermined and relatively short timeframe from the commencement of neoadjuvant therapy. As will be understood, such patients are those whose cancer has progressed to a stage where there are no alternatives and cystectomy is the only option. The patients may have MIBC, or they may have NMIBC at high risk of progression. For such patients, the standard treatment would be cystectomy.

[0100] Therefore, in one embodiment, the therapy of the present invention is used as a novel adjunctive therapy to cystectomy, i.e., prior to such cystectomy, in patients who require such treatment, such as those already diagnosed with MIBC.

[0101] In one embodiment, the present invention therefore provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, for use in a method of neoadjuvant therapy for bladder cancer in a patient scheduled for cystectomy, the method comprising instilling the composition into the patient's bladder, wherein the neoadjuvant therapy is not a method of photodynamic therapy.

[0102] In another embodiment, the present invention provides a method of neoadjuvant therapy for bladder cancer in a patient scheduled for cystectomy, the method comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder, wherein the neoadjuvant therapy is not a method of photodynamic therapy.

[0103] In one embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, the composition for use in a method of treating a patient with MIBC, the method comprising: a) a neoadjuvant therapy, wherein the composition is instilled into the patient's bladder and wherein the neoadjuvant therapy is not photodynamic therapy; and b) performing a cystectomy.

[0104] In another embodiment, the present invention provides a method for treating a patient with MIBC, the method comprising: a) a neoadjuvant therapy, wherein a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof is instilled into the patient's bladder and wherein the neoadjuvant therapy is not photodynamic therapy; and b) performing a cystectomy.

[0105] The time interval between the neoadjuvant therapy of the present invention and the cystectomy can vary, but is preferably from 0 to 6 weeks, for example from 0 to 1, 2, 3, 4, 5 or 6 weeks, more preferably from 0 to 3 weeks, for example 1 week or 2 weeks. “0” means that the cystectomy is performed directly after the neoadjuvant therapy according to the present invention.

[0106] Neoadjuvant therapy can be repeated prior to cystectomy. For example, it can be performed two or more times, such as 3, 4, 5, 6, 7, 8, 9, or 10 times, or more than 10 times. The interval between each treatment can be a few days or a few weeks, such as 4 days to 4 weeks, or 1, 2, or 3 weeks.

[0107] The neoadjuvant therapies of this invention can be administered in combination with other neoadjuvant therapies, for example, before, during, or after other neoadjuvant therapies (such as neoadjuvant radiotherapy, neoadjuvant chemotherapy, and neoadjuvant immunotherapy). Examples of neoadjuvant therapies include neoadjuvant chemotherapy (intravesical infusion or systemic administration) of cisplatin, methotrexate, vinblastine, pentorubicin, doxorubicin, mitomycin C, or combinations thereof, and neoadjuvant immunotherapy of BCG (intravesical infusion or systemic administration).

[0108] Following cystectomy, patients may receive systemic adjuvant chemotherapy, such as cisplatin, methotrexate, vinblastine, doxorubicin, gemcitabine, doxorubicin, epirubicin, cyclophosphamide, or combinations thereof. Alternatively or in addition, patients may receive systemic adjuvant immunotherapy, such as anti-PD-L1 antibodies and / or anti-PD-1 antibodies. Suitable anti-PD-L1 antibodies and / or anti-PD-1 antibodies include those described herein with respect to compositions used in the present invention. Formulations suitable for parenteral (e.g., subcutaneous) or intravenous administration are described in WO 2010 / 077634, WO 2013 / 019906, and WO 2013 / 181452 (for anti-PD-L1 antibodies) and in WO 2004 / 004771, WO 2008 / 156712, WO 2009 / 114335, and WO 2013 / 079174 (for anti-PD-1 antibodies). The entire contents of these documents are incorporated herein by reference.

[0109] The adjuvant or neoadjuvant therapy according to the method of the present invention has several advantages over neoadjuvant radiotherapy, (neo)adjuvant chemotherapy, and (neo)adjuvant immunotherapy, in which nausea, vomiting, fatigue, anemia, epithelial surface damage, intestinal discomfort / gastrointestinal irritation, nephrotoxicity, neurotoxicity, swelling, immune system deterioration, and infertility are well-known and common side effects. In contrast, most reported adverse reactions to HAL (presenting...) Adverse reactions (in the form of) are transient and mild to moderate in intensity. From the use of The most frequently reported adverse reactions in clinical studies were bladder spasms in 2.4% of patients, dysuria in 1.8% of patients, bladder pain in 1.7% of patients, and hematuria in 1.7% of patients.

[0110] Furthermore, HAL has a highly favorable metabolic profile compared to chemotherapeutic agents such as cisplatin. HAL interferes with the body's own heme biosynthesis pathway and causes the accumulation of porphyrins, particularly PpIX, which is the final intermediate in heme synthesis. Since these porphyrins are naturally occurring compounds in the body, there is a "natural process" in the body for degrading (metabolizing) heme and excreting the degraded heme.

[0111] The invention is further illustrated by the following non-limiting embodiments.

[0112] Example

[0113] Example 1 - Therapeutic efficacy of HAL intravesical instillation into the bladder of tumor-bearing rats

[0114] method :

[0115] Superficial bladder tumors were established in female Fischer rats (purchased from Charles River Laboratories, Chatilon-sur-Chalronne, France) weighing 150g-175g using the rat bladder cancer cell line AY-27. As described in J.Urol.190(2),2013,731-736. Animals were used for experiments 5 days after tumor cell inoculation.

[0116] Just before the infusion, freeze-dried HAL (in the form of...) The powder was dissolved in serum-free RPMI medium to a final concentration of 2 mg / ml (8 mM). The resulting solution had a pH of 6.8. 0.5 ml of the solution was instilled into the rat bladder and left in place for approximately 1 hour, then emptied. The bladder was washed three times with PBS. No HAL was instilled into the bladders of control rats. Treatment was administered at normal body temperature.

[0117] Rats were sacrificed 12, 30, or 60 days after treatment with an overdose of pentobarbital. Bladders were removed from the animals and transferred to vials containing 4% formaldehyde, where they were kept for at least 4 hours. The bladders were then cut into four sections and fixed for 48 hours. After different dehydration cycles with gradients of ethanol and xylene, the bladder tissue was embedded in paraffin. 5 μm paraffin-embedded sections were excised and stained with hematoxylin-eosin-safranin (HES) for histological evaluation.

[0118] result :

[0119] The therapeutic efficacy on days 12, 30, or 60 post-inoculation was determined histologically as the degree of tumor regression. Based on the degree of tumor regression, rats were divided into four groups:

[0120] • No response (“NR”): Muscle-invasive tumor.

[0121] • Moderate response (“MR”): Several areas or islands of tumor cells with fewer tumor cells.

[0122] • Near-complete response (“near CR”): a single island of tumor cells or isolated tumor cells.

[0123] • Complete response (“CR”): No tumor cells.

[0124] A good antitumor effect is defined as the sum of "near-CR" and "CR".

[0125] Table 1 presents the results showing the therapeutic efficacy of treatment, including HAL bladder instillation into rats with bladder cancer, compared to the control group, where such treatment was performed in the absence of photoactivated light:

[0126] Table 1

[0127]

[0128]

[0129] The various embodiments of the present invention are as follows:

[0130] Implementation Scheme 1: A method of bladder cancer treatment, the method comprising the step of instilling a composition containing 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into a patient's bladder, and wherein said method is not a method of photodynamic therapy.

[0131] Implementation Scheme 2: The method described in Implementation Scheme 1, wherein the method is performed at body temperature.

[0132] Implementation Scheme 3: The method according to Implementation Scheme 1 or 2, wherein the patient is a person.

[0133] Implementation Scheme 4: The method according to any one of Implementation Schemes 1 to 3, wherein the method is performed in the absence of photoactivating light.

[0134] Implementation Scheme 5: The method according to Implementation Scheme 4, wherein the light-activated light is white light, blue light, red light, or any combination thereof.

[0135] Implementation Scheme 6: The method according to any one of Implementation Schemes 1 to 5, wherein the composition is instilled into the patient's bladder via a catheter and remains in the bladder for a period of about 10 minutes to about 3 hours.

[0136] Implementation Scheme 7: The method according to any one of Implementation Schemes 1 to 6, wherein the concentration of HAL in the composition is in the range of 0.1% to 5% by weight based on the total weight of the composition, or the equivalent concentration of a pharmaceutically acceptable salt of HAL.

[0137] Implementation Scheme 8: The method according to any one of Implementation Schemes 1 to 7, wherein the composition is an aqueous solution of HAL or a pharmaceutically acceptable salt thereof, preferably a solution of HAL or a pharmaceutically acceptable salt thereof in an aqueous buffer solution, more preferably a solution of HAL or a pharmaceutically acceptable salt thereof in a phosphate buffer solution.

[0138] Implementation Scheme 9: The method according to Implementation Scheme 8, wherein the pH of the composition is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.2.

[0139] Implementation Scheme 10: The method according to any one of Implementation Schemes 1 to 9, wherein the composition is a solution of 2 mg / ml HAL hydrochloride in an aqueous buffer containing disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0140] Implementation Scheme 11: The method according to any one of Implementation Schemes 1 to 10, wherein the bladder cancer is muscle-invasive bladder cancer (MIBC).

[0141] Implementation Scheme 12: The method according to any one of Implementation Schemes 1 to 10, wherein the bladder cancer is non-muscle-invasive bladder cancer (NMIBC).

[0142] Implementation Scheme 13: The method according to Implementation Scheme 12, wherein the bladder cancer is NMIBC with a high risk of progression.

[0143] Implementation Scheme 14: The method according to any one of Implementation Schemes 1 to 13, wherein the method is performed in a bladder cancer patient who has undergone transurethral resection.

[0144] Implementation Scheme 15: The method according to any one of Implementation Schemes 1 to 14, the method being used to prevent the recurrence of the bladder cancer.

[0145] Implementation Scheme 16: The method according to any one of Implementation Schemes 1 to 13, wherein the method is an adjunctive therapy, preferably wherein the bladder cancer is NMIBC and the method is performed before or after transurethral resection of NMIBC.

[0146] Implementation Scheme 17: The method according to Implementation Scheme 16, wherein the bladder cancer is NMIBC and the method is performed after transurethral resection of NMIBC.

[0147] Implementation Scheme 18: The method according to Implementation Scheme 16 or 17, wherein the method replaces or partially replaces other adjuvant therapies for treating bladder cancer, preferably wherein the other adjuvant therapies are chemotherapy and / or immunotherapy, such as BCG treatment.

[0148] Implementation Scheme 19: The method according to any one of Implementation Schemes 1 to 13, wherein the method is neoadjuvant therapy, preferably wherein the bladder cancer is MIBC and the method is performed prior to cystectomy.

[0149] Implementation Scheme 20: Use of 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bladder cancer, wherein the medicament is instilled into the bladder of a patient, and wherein the treatment is not photodynamic therapy.

[0150] Implementation Scheme 21: According to the use described in Implementation Scheme 20, the treatment is performed at body temperature.

[0151] Implementation Scheme 22: The use according to Implementation Scheme 20 or 21, wherein the patient is a person.

[0152] Implementation Scheme 23: The use according to any one of Implementation Schemes 20 to 22, wherein the treatment is performed in the absence of photoactivated light.

[0153] Implementation Scheme 24: According to the use described in Implementation Scheme 23, the light-activated light is white light, blue light, red light, or any combination thereof.

[0154] Implementation Scheme 25: The use according to any one of Implementation Schemes 20 to 24, wherein the drug is instilled into the patient's bladder via a catheter and remains in the bladder for a period of about 10 minutes to about 3 hours.

[0155] Implementation Scheme 26: The use according to any one of Implementation Schemes 20 to 25, wherein the concentration of HAL in the drug is based on the total weight of the drug in the range of 0.1% to 5% by weight, or the equivalent concentration of a pharmaceutically acceptable salt of HAL.

[0156] Implementation Scheme 27: The use according to any one of Implementation Schemes 20 to 26, wherein the drug is an aqueous solution of HAL or a pharmaceutically acceptable salt thereof, preferably a solution of HAL or a pharmaceutically acceptable salt thereof in an aqueous buffer solution, more preferably a solution of HAL or a pharmaceutically acceptable salt thereof in a phosphate buffer solution.

[0157] Implementation Scheme 28: According to the use described in Implementation Scheme 27, the pH of the drug is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.2.

[0158] Implementation Scheme 29: The use according to any one of Implementation Schemes 20 to 28, wherein the drug is a solution of 2 mg / ml HAL hydrochloride in an aqueous buffer containing disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0159] Implementation Scheme 30: The use according to any one of Implementation Schemes 20 to 29, wherein the bladder cancer is muscle-invasive bladder cancer (MIBC).

[0160] Implementation Scheme 31: The use according to any one of Implementation Schemes 20 to 29, wherein the bladder cancer is non-muscle-invasive bladder cancer (NMIBC).

[0161] Implementation Scheme 32: The use according to Implementation Scheme 31, wherein the bladder cancer is NMIBC with a high risk of progression.

[0162] Implementation Scheme 33: The use according to any one of Implementation Schemes 20 to 32, wherein the treatment is performed in a bladder cancer patient who has undergone transurethral resection.

[0163] Implementation Scheme 34: The use according to any one of Implementation Schemes 20 to 33, wherein the treatment is for preventing recurrence of the bladder cancer.

[0164] Implementation Scheme 35: The use according to any one of Implementation Schemes 20 to 32, wherein the treatment is an adjunctive therapy, preferably wherein the bladder cancer is NMIBC and the use is performed before or after transurethral resection of NMIBC.

[0165] Implementation Scheme 36: The use according to Implementation Scheme 35, wherein the bladder cancer is NMIBC and the treatment is performed after transurethral resection of NMIBC.

[0166] Implementation Scheme 37: The use according to Implementation Scheme 35 or 36, wherein the treatment replaces or partially replaces other adjuvant therapies for the treatment of bladder cancer, preferably wherein the other adjuvant therapies are chemotherapy and / or immunotherapy, such as BCG treatment.

[0167] Implementation Scheme 38: The use according to any one of Implementation Schemes 20 to 32, wherein the treatment is a neoadjuvant therapy, preferably wherein the bladder cancer is MIBC and the treatment is performed prior to cystectomy.

Claims

1. A composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, said composition for use in a method of bladder cancer therapy, said method comprising instilling said composition into a patient’s bladder, and said method not being a method of photodynamic therapy.

2. The composition used according to claim 1, wherein the method is performed at body temperature.

3. The composition used according to claim 1 or claim 2, wherein the patient is a human.

4. The composition used according to any one of the preceding claims, wherein the method of the therapy is performed in the absence of photoactivated light.

5. The composition used according to claim 4, wherein the photoactivated light is white light, blue light, red light, or any combination thereof.

6. The composition used according to any one of the preceding claims, wherein the composition is instilled into the patient's bladder via a catheter and remains in the bladder for a period of about 10 minutes to about 3 hours.

7. The composition used according to any one of the preceding claims, wherein the concentration of HAL in the composition is in the range of 0.1% to 5% by weight based on the total weight of the composition, or the equivalent concentration of a pharmaceutically acceptable salt of HAL.

8. The composition used according to any one of the preceding claims, wherein the composition is an aqueous solution of HAL or a pharmaceutically acceptable salt thereof, preferably a solution of HAL or a pharmaceutically acceptable salt thereof in an aqueous buffer solution, more preferably a solution of HAL or a pharmaceutically acceptable salt thereof in a phosphate buffer solution.

9. The composition according to claim 8, wherein the pH of the composition is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.

2.

10. The composition used according to any one of the preceding claims, wherein the composition is a solution of 2 mg / ml HAL hydrochloride in an aqueous buffer solution comprising disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

11. The composition used according to any one of the preceding claims, wherein the bladder cancer is muscle-invasive bladder cancer (MIBC).

12. The composition used according to any one of claims 1 to 10, wherein the bladder cancer is non-muscle-invasive bladder cancer (NMIBC).

13. The composition used according to claim 12, wherein the bladder cancer is NMIBC with a high risk of progression.

14. The composition used according to any one of the preceding claims, wherein the method of treatment is performed in a bladder cancer patient who has undergone transurethral resection.

15. The composition used according to any one of the preceding claims, the composition being used to prevent recurrence of the bladder cancer.

16. The composition used according to any one of claims 1 to 13, wherein the method of the therapy is adjunctive therapy, preferably wherein the bladder cancer is NMIBC and the method of the therapy is performed before or after transurethral resection of NMIBC.

17. The composition used according to claim 16, wherein the bladder cancer is NMIBC and the method of the therapy is performed after transurethral resection of NMIBC.

18. The composition used according to claim 16 or claim 17, wherein the method of treatment replaces or partially replaces other adjuvant therapies for treating bladder cancer, preferably wherein the other adjuvant therapies are chemotherapy and / or immunotherapy, such as BCG treatment.

19. The composition used according to any one of claims 1 to 13, wherein the method of the therapy is neoadjuvant therapy, preferably wherein the bladder cancer is MIBC and the method of the therapy is performed prior to cystectomy.

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