Bladder cancer treatment

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 treating bladder cancer, the method comprising intravenous infusion of the composition into the patient's bladder, and the method is not a photodynamic therapy method.

Description

Technical Field

[0001] The present invention relates to a therapy for bladder cancer. More specifically, it relates to a therapy for bladder cancer in which hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof is infused into a patient's bladder without performing photodynamic therapy (PDT).

[0002] Such a therapy is used as a therapeutic treatment for bladder cancer and as a preventive treatment for preventing its recurrence. It can be used as a single therapy or in combination with other therapies and / or surgical procedures, such as radiotherapy, chemotherapy, immunotherapy, transurethral resection (TUR), or as an adjuvant or neoadjuvant therapy in combination with radical cystectomy.

Background Art

[0003] Bladder cancer is the ninth most common cancer diagnosis worldwide, with over 330,000 new cases and over 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 depends on cystoscopic examination (cystoscopy) of the bladder and histological evaluation of the excised 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 undergoes transurethral resection (TUR), a procedure in which the bladder is visualized through the urethra and the tumor and lesion are removed. In the case of non-minor bladder cancer (NMIBC), such resection aims to completely remove the tumor. In the case of minor bladder cancer (MIBC), such resection is of a palliative nature. Apart from tumor removal, TUR is also performed to allow for an accurate histological diagnosis of bladder cancer based on examination of the resected tumor / tumor biopsy by a pathologist.

[0006] For patients with MIBC, the standard treatment is radical cystectomy, i.e., removal of the bladder and adjacent organs, namely the prostate and seminal vesicles in males, and the uterus and adnexa in females. This also involves the dissection of local lymph nodes. Cystectomy is also suggested for patients with NMIBC at high risk of progression, i.e., patients with multiple recurrent high-grade tumors or high-grade T1 tumors, or high-grade tumors complicated with carcinoma in situ (CIS). Furthermore, cystectomy is suggested for NMIBC patients who have received Bacillus Calmette-Guerin (BCG) immunotherapy but have experienced failure of such treatment.

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

[0008] In neoadjuvant radiotherapy, it takes approximately 4–6 weeks for cancer to downstage after radiotherapy. However, delays of more than 90 days in surgery in patients with locally advanced bladder cancer have been shown to cause a significant increase in extravesical disease (81% vs. 52%). Neoadjuvant radiotherapy is not recommended according to current European guidelines for MIBC because there is no data to support the idea that neoadjuvant radiotherapy increases survival for surgically treatable MIBC.

[0009] Neoadjuvant chemotherapy offers several advantages, including the provision of chemotherapy at the earliest possible time when the burden of micrometastatic disease is expected to be low, the expected better tolerance of chemotherapy before cystectomy than after, and the hypothetical possibility that patients with micrometastatic disease may respond to neoadjuvant therapy and reveal a favorable pathological state, primarily determined by negative lymph node status and negative surgical margins. Neoadjuvant cisplatin-containing chemotherapy has been shown to significantly improve survival (an absolute improvement of 5% in survival at 5 years). However, as mentioned above, delays in cystectomy can impair outcomes in patients who are not sensitive to chemotherapy, and generally, preoperative anemia and neuropathy are more common in patients receiving neoadjuvant chemotherapy before cystectomy. Current European guidelines on MIBC state that "neoadjuvant chemotherapy has limitations in terms of patient selection, developments in current surgical techniques, and combinations of current chemotherapy." Therefore, there is room for improvement in neoadjuvant therapy for bladder cancer patients scheduled for cystectomy, i.e., bladder cancer patients diagnosed with MIBC or NMIBC at high risk of progression, including multiple recurrent high-grade tumors, high-grade T1 tumors, or high-grade tumors complicated with carcinoma in situ (CIS).

[0010] For patients with NMIBC, the standard treatment is tumor resection by TUR. Visualization of bladder cancer during cystoscopy and / or TUR can be improved by intravenous infusion of compositions containing HAL or pharmaceutically acceptable salts thereof into the bladder and exposure of the inside of the bladder to blue light. Standard procedures involve performing cystoscopy and TUR using white light. However, because the use of white light can miss lesions that are present but not visible, photodynamic diagnosis / detection (PDD) is often used in such procedures. Generally, PDD involves the administration of a photosensitizer or its precursor (collectively referred to herein as “photosensitizer”) to the region of interest. The photosensitizer or its precursor is taken up into the cell, and the photosensitizer precursor is converted to the photosensitizer. When the region of interest is exposed to light of a suitable wavelength, the photosensitizer is activated (i.e., excited), and when it relaxes to the ground state, fluorescence is produced and detected.

[0011] Hexyl 5-ALA ester (hexaaminolevulinic acid, HAL) and its salts are known precursors of photosensitizers. HAL preferably penetrates rapidly growing cells, such as tumor cells, and is converted to the photosensitizer porphyrin (e.g., protoporphyrin IX, "PpIX"). Upon blue light activation, the porphyrin is activated and, upon relaxation to the ground state, emits red light, thus enabling specific and accurate visualization of tumors. Hexvix® (Photocure ASA, Norway), marketed as Cysview® in the United States and Canada, is a commercially approved drug containing HAL and is used in PDD during cystoscopy and TUR procedures.

[0012] In patients with NMIBC, HAL-guided cystoscopy and TUR increase the detection of both papillary neoplasms and squamous carcinoma in situ (CIS) lesions, the latter of which are difficult to detect with white light alone. HAL-guided TUR for bladder cancer in patients with NMIBC further reduces the rate of residual tumor after such procedures and results in superior recurrence-free survival (RFS) rates and extended RFS intervals compared to white light TUR alone (see Rink M, et al., Eur Urol 4(64), 2013, 624). Existing European guidelines and consensus statements from several expert groups on NMIBC recommend the use of HAL-guided TUR in various settings of NMIBC management, some even recommending its use in all NMIBC patients in initial TUR (see Witjes JA, et al., Eur Urol 1(66), 2014, 863).

[0013] TaT1 tumors can be completely resected by HAL-induced transurethral resection (TUR), and HAL-induced TUR has a favorable effect on the recurrence rate; however, these tumors may recur in a limited number of cases and progress to muscle-invasive bladder cancer. Therefore, adjuvant therapy, i.e., adjuvant chemotherapy, or adjuvant chemotherapy and adjuvant immunotherapy, should be considered in all patients. The choice of therapy may be considered differently depending on what risks are acceptable for the individual patient. Typically, patients receive a single immediate intravesical infusion of chemotherapy into the bladder after TUR. 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 to these patients before recurrence. However, for other patients, the likelihood of recurrence and / or progression is considerably higher, and a single immediate infusion remains incomplete treatment. No single chemotherapy agent is superior in terms of efficacy. Mitomycin C, epirubicin, and doxorubicin all showed beneficial effects. However, mitomycin C (MMC) is the drug of choice.

[0014] According to the EAU guidelines for the treatment of NMIBC, in patients with TaT1 tumors at moderate or high risk of recurrence and moderate or high risk of progression, a single immediate intravenous infusion of chemotherapy should be followed by at least one year of Calmette-Guérin bacillus (BCG) immunotherapy or further intravenous chemotherapy. In patients with bladder CIS, at least one year of intravesical BCG is prescribed.

[0015] Assuming that maintenance therapy with BCG is necessary for optimal efficacy, the issue of BCG toxicity becomes more relevant. There remains resistance to the use of BCG due to its more pronounced side effects compared to intravesical chemotherapy. Its use is jeopardized by the high frequency of deaths due to BCG sepsis, as well as BCG-induced cystitis and allergic reactions. Furthermore, BCG treatment failure is not uncommon.

[0016] Photodynamic therapy (PDT) has also been proposed for the treatment of bladder cancer, and clinical studies are being conducted to investigate the efficacy and safety of such treatments. Similar to PDD, PDT involves the administration of a photosensitizer to the region of interest, followed by the activation of the photosensitizer with light of a suitable wavelength (i.e., photoactivating light) to induce the PDT effect. The therapeutic effect of PDT is based on a phototoxic response. The photosensitizer is taken up by cells, and if the drug is a precursor of the photosensitizer, the precursor is converted into the photosensitizer. When the region of interest is exposed to photoactivating light, the photosensitizer is activated, i.e., excited from the ground singlet state to the excited singlet state. It then undergoes intersystem crossing to a more permanent excited triplet state. One of the few chemical species present in tissue in the ground triplet state is molecular oxygen. If the activated photosensitizer and an oxygen molecule are in close proximity, energy transfer may occur, causing the activated photosensitizer to relax to its ground singlet state and generating an excited singlet state oxygen molecule. Singlet oxygen is a highly invasive chemical species that reacts rapidly with nearby biomolecules. Ultimately, these reactions kill cells, namely cancer cells.

[0017] HAL and its salts have been proposed for use in PDT for bladder cancer (see, for example, U.S. Patent Application Publication 2005 / 0031541, Example 21). HAL and its salts have also been proposed for use in PDT for bladder cancer, where HAL is infused intravenously into the patient's bladder and the inside of the bladder is exposed to blue light (see International Publication No. 2017 / 103285 and U.S. Patent Application Publication No. 2019 / 0022404), for use in neoadjuvant therapy for bladder cancer in patients scheduled for cystectomy, where HAL is infused intravenously into the patient's bladder and the inside of the bladder is exposed to light (International Publication No. 2017 / 103283 and U.S. Patent Application Publication No. 2018 / 0369379), and for use in the therapy of bladder cancer, where a combination of HAL and an anti-PD-L1 and / or anti-PD-1 antibody is infused intravenously into the patient's bladder and the inside of the bladder is exposed to light (International Publication No. 2017 / 103280). Bader et al. (Urol. Oncol. Seminars and Original Investigations 31, 2013, 1178-1183) performed HAL PDT using HAL solutions (8 mM and 16 mM). Irradiation was performed using white light from a xenon bulb, transmitted to the bladder via a glass fiber inserted into the working channel of a cystoscope. Photoactivation light is used in all of these early methods of PDT using HAL and its salts.

[0018] Some of the drawbacks of the PDT method described above are that it requires specially designed equipment that is not commercially available to perform the procedure. Furthermore, the use of optical fibers and positioning the tip of the fiber in the center of the bladder is complex and cumbersome. The position of the fiber tip needs to be confirmed by ultrasound, or the PDT procedure needs to be interrupted to ensure that the fiber tip remains in the center and does not come into contact with the bladder wall, which could lead to injury. In addition, side effects occur frequently, and depending on the PDT parameters used, it can take a long time for the side effects to resolve.

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

[0020] As described in Saleh Al-Omari, Biophys. Rev. (2013) 5:305-311, researchers have reported on the dark toxicity of certain photosensitizers in cell lines. Dark toxicity refers to the cytotoxicity of photosensitizers to cancer cells in the absence of light irradiation. None of the studies described by Saleh Al-Omari in this paper concern HAL (or 5-ALA or 5-ALA derivatives), and all studies investigate dark toxicity in cell culture.

[0021] In Example 21 of U.S. Patent Application Publication No. 2015 / 0191419, the dark toxicity of HAL was determined in WiDr cells derived from primary adenocarcinoma of the rectosigmoid colon. HAL was added to the cell culture medium at a concentration of 0.001–1 mM. Weak cytotoxicity was observed in the range of 0.3–1 mM with a minimum cell viability of 85%, i.e., less than 15% of cells were killed.

[0022] Neither Saleh Al-Omari nor U.S. Patent Application Publication 2015 / 0191419 has reported any investigation into the dark toxicity of HAL in bladder cancer cell lines. Studies conducted in vitro on cell lines, i.e., on isolated tumor cells, do not reflect the reality in patients (e.g., bladder cancer patients) where the tumor is surrounded by a tumor microenvironment that can affect the effectiveness of any treatment. Therefore, known dark toxicity studies have revealed nothing regarding the dark toxicity of HAL or its salts to bladder tumors in patients.

[0023] U.S. Patent Application Publication No. 2013 / 0158293 relates to enhancers for cancer hyperthermia containing 5-ALA and 5-ALA derivatives. Hyperthermia is a therapeutic method that inhibits the proliferation of cancer cells by taking advantage of the fact that cancer cells are more heat-sensitive than normal cells. At a temperature of 42°C (i.e., higher than body temperature), 5-ALA has been shown to exhibit anticancer effects in various cell lines in the absence of photodynamic therapy, i.e., without light irradiation. However, results are not provided for HAL or any of its salts (or other 5-ALA derivatives such as 5-ALA esters). Furthermore, this document does not mention the potential treatment of bladder cancer. [Overview of the project]

[0024] As demonstrated herein, the applicant has surprisingly found that intravesical (i.e., internal to the bladder) administration of hexyl 5-ALA ester (HAL) is effective in eradicating tumors in the bladder or reducing their growth in the absence of photodynamic therapy, i.e., in the absence of photoactivating light. As a result of this finding, the applicant proposes the use of HAL or a pharmaceutically acceptable salt thereof as a therapy for treating bladder cancer or reducing its recurrence, without concomitant use of photoactivating light. While not wishing to be bound by theory, it is assumed that the therapy according to the present invention is effective in stimulating the patient's immune system, thereby not only combating bladder cancer but also reducing its recurrence rate after treatment.

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

[0026] Since this therapy is performed in the absence of photoactivating light, it addresses the problems associated with conventional PDT methods where delivery of light to the inside of the patient's bladder can be complex and cumbersome and requires the use of a specially designed device to perform PDT. Furthermore, the use of HAL or its pharmaceutically acceptable salts without photoactivating light is expected to be well tolerated by patients with minimal side effects.

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

[0028] In another aspect, the present invention provides a method of treating bladder cancer, the method comprising the step of instilling a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient, the method not being a method of photodynamic therapy.

BRIEF DESCRIPTION OF THE INVENTION

[0029] Definitions As used herein, the term "photodynamic therapy" or "PDT" refers to a treatment involving the combination of (i) a photosensitizing agent, and (ii) photoactivating light, i.e., light of an appropriate wavelength for activating the photosensitizer and converting it to a therapeutically active form. The photosensitizing agent can be a photosensitizer or a precursor of a photosensitizer. In some cases, the photosensitizing agent is a precursor of a photosensitizer that can be administered to a patient and converted in vivo to a photosensitizer. Hexyl 5-ALA ester (HAL) is an example of a precursor of the photosensitizer protoporphyrin IX ("PpIX"). PDT involves the administration of a photosensitizing agent to a treatment area, and then the treatment area is exposed to photoactivating light. The photosensitizer is therapeutically inactive until exposed to photoactivating light. The photosensitizer is converted to a therapeutically active form only after exposure to photoactivating light (i.e., "photoactivation"). Light that can activate the photosensitizer and convert it to a therapeutically active form (i.e., "photoactivating light") is thus an essential component of any method of photodynamic therapy. As will be understood, the nature of the photoactivating light varies depending on the photosensitizer. In order to achieve the desired photoactivation and thus the intended therapeutic effect, the light must be provided at a specific dose (i.e., light dose) and at a suitable defined wavelength and fluence rate.

[0030] As used herein, the term "cancer" refers to abnormally proliferating cells. The proliferation of such cells typically causes the formation of a tumor. The term "tumor" as used herein refers to an abnormal mass of tissue that includes cancerous cells.

[0031] Cancer cells can be benign, pre-malignant or malignant. Such cells can be invasive and / or have the ability to metastasize to other locations within the body. The term cancer as used herein includes cancerous growths, tumors, and their metastases.

[0032] As used herein, 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). There, they can settle and proliferate within the normal tissues. When tumor cells metastasize, the new tumor may be called metastatic cancer.

[0033] As used herein, the term “bladder cancer” refers to cancer arising from the tissue of the bladder. Bladder cancer is classified according to the extent of cancer spread (i.e., stage) and graded based on how abnormally and invasively the cells appear under a microscope. Staging is usually performed using transurethral resection (TUR) and radiographic imaging (e.g., CT or MRI) of the bladder tumor. Papillary tumors that are confined to the mucosa or invade the lamina propria are classified as Ta or T1. Flat lesions that do not invade the basement membrane of the bladder mucosa are called Tis (intraepithelial). All three categories (Tis, Ta, and T1) are classified together as non-muscle-invasive disease, i.e., non-muscle-invasive bladder cancer (NMIBC), for therapeutic purposes. 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 reduction, mitigation, or elimination of a disease. Palliative treatment includes treatment intended to minimize or partially or completely inhibit the onset of the disease. In the context of this invention, the disease is bladder cancer.

[0035] As used herein, “prevention” means absolute prevention, i.e., maintaining a normal level of the severity or appearance of a particular symptom of a disease, or reducing or mitigating the severity or timing (e.g., delay) of the onset of such symptom.

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

[0037] As used herein, “therapeutic effective dose” refers to the amount of a therapeutic or prophylactic agent that produces a desired therapeutic effect, i.e., an amount of a therapeutic or prophylactic agent that is effective in achieving the intended purpose. Such a dose may be provided by a single dose or multiple (e.g., repeated) doses of any of the agents described herein. For example, it may be necessary to administer several doses of any of the agents described herein to constitute a “therapeutic effective dose” that produces a desired therapeutic effect. While the needs of individual patients may vary, determining the optimal range of effective doses of the agents described herein is within the capabilities of those skilled in the art. In general, a dosage regimen for treating a disease using any of the agents described herein may be selected by those skilled in the art according to various factors, including the degree and severity of the disease.

[0038] As used herein, the term “patient” refers to a human subject receiving treatment from a clinician.

[0039] As used herein, the term "hexyl 5-ALA ester" (HAL) means n-hexyl aminolevrinate, i.e., n-hexyl 5-amino-4-oxo-pentanoate.

[0040] As used herein, the term “pharmaceutically 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 herein, the term “adjuvant therapy” refers to the administration of a therapeutic or prophylactic agent in addition to the primary treatment for a disease.

[0042] As used herein, the term “neoadjuvant therapy” refers to the administration of a therapeutic or prophylactic agent prior to (i.e., prior to) the primary treatment for a disease.

[0043] The therapy for bladder cancer according to the present invention is not a photodynamic therapy method, i.e., it does not rely on the activation of a photosensitizer by photoactivating light. It may also be referred to as "non-photodynamic." In contrast to known methods involving the use of HAL or its salts in the treatment of bladder cancer, the therapy described herein relies on the effects of HAL or its pharmaceutically acceptable salts in the absence of photoactivating light. The therapy does not involve the delivery of photoactivating light into the inside of the patient's bladder following intravesical (i.e., inside the bladder) administration of one of HAL or its pharmaceutically acceptable salts.

[0044] The composition used in this invention does not require photodynamic therapy to achieve this therapeutic effect and can suppress or delay tumor growth in the patient's bladder and / or prevent tumor recurrence. Specifically, the composition is used in a photoactivation-free method that can generate a therapeutically active form of the photosensitizer PpIX in vivo.

[0045] Wavelengths of light generally considered suitable for generating the therapeutically active form of the photosensitizer PpIX in vivo after administration of HAL or a pharmaceutically acceptable salt thereof include white light, i.e., visible light with a wavelength of about 350 to about 700 nm; blue light, i.e., light with a wavelength of about 360 to about 450 nm; and red light, i.e., light with a wavelength of about 600 to about 670 nm. The therapeutic method according to the present invention is performed without exposing the inside of the patient's bladder to white light, blue light, red light, or any combination thereof, and two or more wavelengths of light are used simultaneously (i.e., at the same time) or sequentially (i.e., consecutively with each other). The amount of light delivered during irradiation of the inside of the bladder with white light and / or red light and / or blue light during PDT may vary. Typically, these are 0.01 to 100 J / cm². 2 The fluence rate used during PDT, when illuminating the inside of the bladder with white light and / or red light and / or blue light, can vary. The duration of light exposure in conventional PDT methods varies. Typically, light may be provided for about 10 to 30 minutes.

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

[0047] A composition containing HAL or a pharmaceutically acceptable salt thereof for use in the present invention is preferably administered intravenously to the patient's bladder via a catheter. Preferably, the composition is retained in the bladder for a predetermined period of time. The patient's bladder is preferably empty at the time of intravenous administration and, if necessary, may be emptied before the intravenous administration of the composition.

[0048] The composition, once administered intravenously into the patient's bladder, can be retained in the bladder for a predetermined period. A suitable period can be easily determined by those skilled in the art. The composition may be left in the bladder for, for example, about 10 minutes to about 3 hours, preferably about 20 minutes to about 2 hours, and more preferably about 30 minutes to 1 hour. Advantageously, the composition may be retained in the patient's bladder for about 30 minutes or more, or about 1 hour or more. At the end of this period, the bladder is emptied. If the patient is unable to retain the composition for a suitable period, for example, about 10 minutes, or about 20 minutes, or about 30 minutes, or about 1 hour, the intravenous infusion procedure may be repeated.

[0049] In one embodiment, the composition is administered intravenously into the patient's bladder through a catheter and left in the bladder for about 30 minutes or about 1 hour. The bladder is then emptied.

[0050] The compositions used in the present invention comprise hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof. The synthesis of hexyl 5-ALA ester is known in the art. For example, it can be prepared as described in International Publication No. 96 / 28412, the entire contents of which are incorporated herein by reference. For example, hexyl 5-ALA ester can be prepared by reacting 5-ALA with hexanol in the presence of a catalyst such as an acid. Alternatively, hexyl 5-ALA ester hydrochloride is commercially available, for example, in the form of Hexvix® (e.g., available from Photocure ASA) or Cysview® (e.g., available from Photocure Inc.).

[0051] The hexyl 5-ALA ester used in the present invention can be used in the form of a pharmaceutically acceptable salt. Such salts are preferably acid addition salts with 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 International Publication No. 2005 / 092838, the full contents of which are incorporated herein by reference. The preferred acid addition salt of HAL used in the present invention is the hydrochloride salt. The synthetic procedure for salt formation is conventional in the art and is described, for example, in International Publication No. 2005 / 092838.

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

[0053] The compositions used in the present invention are pharmaceutical compositions and may contain pharmaceutically acceptable carriers or excipients, such as stabilizers. The compositions are preferably liquid compositions, more preferably suspensions, and 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 the present 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 phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide, and water.

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

[0057] When the composition used in the present 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 a lyophilized form and is reconstituted before use in a liquid carrier, preferably water or an aqueous solution, most preferably an aqueous buffer.

[0059] In one embodiment, the composition used in the present invention is Hexvix®, i.e., a solution of HAL hydrochloride (2 mg / mL, 8 mM) in an aqueous buffer containing disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide, and water.

[0060] The amount of composition administered intravenously to the patient's bladder may vary depending on the patient's bladder capacity. A suitable amount can be easily determined by those skilled in the art. Generally, an amount of about 50 mL of the composition may be suitable. For example, an amount of about 50 mL of a composition containing 0.2% HAL hydrochloride (8 mM) is suitable and sufficient. The use of an amount of about 50 mL of Hexvix® is considered suitable.

[0061] In one embodiment, the composition for intravenous infusion into the patient's bladder is a solution containing 2 mg / mL of 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 cell death ligand 1). 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 may enable T cell activation, restoring their ability to effectively detect and attack bladder cancer cells. Anti-PD-1 is a monoclonal antibody that binds to the PD-1 (programmed cell 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 thought to restore the anti-cancer T cell response. Therefore, anti-PD-L1 antibodies and anti-PD-1 antibodies target different components of the same interaction mechanism between immune cells (particularly killer 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, namely PD-1, expressed on killer T cells. As can be understood, the anti-PD-L1 antibodies and anti-PD-1 antibodies referred to herein act to inhibit PD-L1 and PD-1, respectively. Thus, they may also be referred to as antagonistic anti-PD-L1 antibodies and antagonistic anti-PD-1 antibodies.

[0063] Accordingly, in another embodiment, the present invention provides a composition for use in a method of treating bladder cancer, the composition comprising (i) hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof, and (ii) an anti-PD-L1 antibody and / or an anti-PD-1 antibody, the method comprising intravenous infusion of the composition into the bladder of a patient, and furthermore, the method is not a method of photodynamic therapy.

[0064] In another embodiment, the present invention provides a method for treating bladder cancer, the method comprising the step of intravenously infusing a composition comprising (i) hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof and (ii) an anti-PD-L1 antibody and / or an anti-PD-1 antibody into the bladder of a patient, the method being not a photodynamic therapy method.

[0065] The preferred anti-PD-L1 antibody for use in the present invention is that of Roche, preferably MPDL3280A. Such anti-PD-L1 antibodies are described in International Publication Nos. 2010 / 077634, 2013 / 019906, and 2013 / 181452, the full contents of which are incorporated herein by reference.

[0066] The preferred anti-PD-1 antibody for use in the present invention is one manufactured by Merck, preferably pembrolizumab (Keytruda). Such anti-PD-1 antibodies are described in International Publication Nos. 2008 / 156712, 2009 / 114335, and 2013 / 079174, the full contents of which are incorporated herein by reference.

[0067] Other preferred anti-PD-1 antibodies used in the present invention are those manufactured by Bristol-Myers Squibb, preferably nivolumab (Opdivo). Such anti-PD-1 antibodies are described in International Publication No. 2004 / 004771, the full contents of which are incorporated herein by reference.

[0068] If the composition used in the present invention further comprises an anti-PD-L1 antibody and / or an anti-PD-1 antibody, these are present in a therapeutically effective amount. The exact amount depends on various factors, including the selected anti-PD-L1 antibody and / or anti-PD-1 antibody, whether the therapy is intended for the treatment and / or prevention of bladder cancer, whether the therapy is a standalone therapy, or whether it is intended to be administered as an adjuvant or neoadjuvant therapy in combination with other therapies and / or surgical procedures, such as those described herein. The therapeutically effective amount of the anti-PD-L1 antibody and / or anti-PD-1 antibody can be readily determined by those skilled in the art, taking such factors into consideration.

[0069] The method for treating bladder cancer 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 of treatment, i.e., a patient diagnosed with bladder cancer.

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

[0071] In one embodiment, bladder cancer is MIBC, where the cancer has entered the muscle layer of the bladder.

[0072] In one embodiment, bladder cancer is NMIBC, where the cancer does not extend to the muscular layer of the bladder. This cancer manifests as papillary tumors and squamous lesions (carcinoma in situ, CIS).

[0073] In one embodiment, bladder cancer is a high-risk NMIBC, including, for example, multiple recurrent high-grade tumors, high-grade T1 tumors, or high-grade tumors complicated with carcinoma in situ (CIS).

[0074] When used for the treatment of bladder cancer, the therapy according to the present invention may be administered once or repeatedly, depending on the stage and invasiveness of the cancer. For example, it may be administered two or more times, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 times, with intervals between treatments. In some cases, it may be administered more than 10 times. The interval between treatments may vary, but may range, for example, from about 4 days to 4 weeks, and may be, for example, 1, 2, or 3 weeks. In some embodiments, the therapy according to the present invention is administered repeatedly in the form of induction therapy followed by maintenance therapy. In some embodiments, induction therapy includes administering the method of therapy according to the present invention two or more times, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 times, e.g., 5, 6, 7, or 8 times, with intervals between treatments of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, e.g., 6, 7, 8, 9, or 10 days. For example, induction therapy may include administering the therapeutic method according to the present invention once a week for a period of about six weeks. In some embodiments, maintenance therapy includes administering the therapeutic method according to the present invention once a week for a period of two, three, or four weeks. Such maintenance therapy may be administered once, two, three, or four times a year.

[0075] The method for treating bladder cancer according to the present invention can be used as a standalone treatment for bladder cancer. Preferably, it can be used as an adjuvant therapy in the treatment of bladder cancer, that is, in addition to the first-line (i.e., primary) therapy for bladder cancer.

[0076] In further embodiments, the present invention provides a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of adjuvant therapy for bladder cancer, the method comprising intravenous infusion of the composition into the patient's bladder, the method not being a method of photodynamic therapy.

[0077] In another embodiment, the present invention provides a method for adjuvant therapy for bladder cancer, The method involves intravenously infusing a composition containing hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder, and the method is not a photodynamic therapy method.

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

[0079] For patients with NMIBC, such as those with TaT1 tumors with a low risk of recurrence and progression, or TaT1 tumors with a moderate or high risk of recurrence and a moderate risk of progression, or patients with CIS, the primary treatment for such patients is typically transurethral resection (TUR), a procedure in which a cystoscope is used to visualize the inside of the bladder through the urethra, detect and identify tumors and lesions, and resect such tumors and lesions. The adjuvant therapy according to the present invention may be performed either before or after TUR, or both before and after TUR.

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

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

[0082] In one embodiment, the therapeutic method of the present invention is performed as adjuvant therapy for TUR in patients who require such treatment, namely, patients diagnosed with NMIBC or suspected to have NMIBC.

[0083] In one embodiment, the adjuvant therapy of the present invention may be performed after TUR. When performed after TUR, the adjuvant therapy for treating NMIBC comprises intravenous infusion of a composition containing hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of the patient who has undergone TUR. In one embodiment, the adjuvant therapy of the present invention is performed immediately after TUR. In another embodiment, the adjuvant therapy of the present invention is performed as a separate treatment after TUR, for example, several days, weeks, or months after the TUR procedure. For example, the adjuvant therapy of the present invention may be performed 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more after, or 1, 2, 3, 4, or 5 weeks or more after, or 1, 2, 3, 4, 5, or 6 months after.

[0084] In another embodiment, the adjuvant therapy of the present invention may be administered prior to TUR. When administered prior to TUR, the adjuvant therapy for treating a patient suspected of having NMIBC comprises intravenous infusion of a composition containing hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of such patient. In one embodiment, the adjuvant therapy of the present invention is administered immediately before TUR. In another embodiment, the adjuvant therapy of the present invention is administered prior to TUR, for example, several days, weeks, or months before the TUR procedure, as a separate treatment. For example, the adjuvant therapy of the present invention may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more prior to TUR, or 1, 2, 3, 4, or 5 weeks or more prior to TUR, or 1, 2, 3, 4, 5, or 6 months prior.

[0085] Any conventional transurethral resection (TUR) procedure for the treatment of NMIBC or suspected NMIBC may be used as the primary treatment. Such procedures may involve, for example, photodynamic detection of lesions in the bladder using HAL or a pharmaceutically acceptable salt thereof with blue light. A TUR procedure typically involves the use of a cystoscope, exposure of the inside of the patient's bladder to white light from the cystoscope for visual inspection to detect and identify lesions, and subsequent excision of the lesions. In some cases, a TUR procedure may involve photodynamic detection (PDD) of lesions. If the TUR procedure involves photodynamic detection of the lesion, the TUR procedure may include: a) intravenous infusion of a composition containing hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder; b) exposure of the inside of the bladder to white light for visual inspection, followed by exposure of the inside of the bladder to blue light for fluorescence detection of the lesion; c) exposure of the bladder to white light for excision of the lesion; and d) optionally monitoring the integrity of the excision by again exposing the inside of the bladder to blue light for fluorescence detection of any remaining lesion.

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

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

[0088] In yet another embodiment, the present invention provides a composition comprising hexyl 5-ALA 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 adjuvant therapy including intravenous infusion of the composition into the bladder of the patient, the adjuvant therapy being a method other than photodynamic therapy, and subsequently performing transurethral resection of the NMIBC.

[0089] In yet another embodiment, the present invention provides a method for treating a patient suspected of having NMIBC, the method comprising administering an adjuvant therapy, which includes intravenous infusion of a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder, the adjuvant therapy being a method other than photodynamic therapy, followed by transurethral resection of the NMIBC.

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

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

[0092] Adjuvant therapy for NMIBC or suspected NMIBC according to the present invention may be administered once or repeatedly. For example, it may be administered two or more times, e.g., three, four, five, six, seven, eight, nine, or ten times, or more than ten times, with intervals of several days or several weeks, e.g., four days to four weeks, or one, two, or three weeks between each treatment.

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

[0094] In one embodiment, the therapy for treating NMIBC of the present invention can be used in combination with systemic or intravesical administration of chemotherapy, such as cisplatin, methotrexate, vinblastine, barrubicin, adriamycin, or mitomycin C, which are suitable for NMIBC, and / or in combination with immunotherapy agents suitable for NMIBC, such as systemic administration of an anti-cancer vaccine or intravesical administration of Bacillus calmette-Guérin (BCG).

[0095] Alternatively, the adjuvant therapy for treating NMIBC according to the present invention may replace or partially replace other adjuvant therapies such as chemotherapy and / or immunotherapy. In one embodiment, the adjuvant therapy according to the present invention replaces or partially replaces other intravesical adjuvant therapies, such as mitomycin and / or BCG. In one embodiment, the adjuvant therapy for treating NMIBC according to the present invention partially or completely replaces BCG. BCG treatment is typically initiated several weeks after transurethral resection of NMIBC and administered once weekly for six weeks, followed optionally by maintenance periods administered once weekly for three weeks at, for example, three months, six months, and twelve months. The adjuvant therapy according to the present invention may replace one, two, three, four, five, or six of such BCG treatments and / or maintenance BCG treatments.

[0096] Up to 40% of patients with NMIBC fail intravesical BCG therapy. The majority of low-grade NMIBCs are prone to recurrence, but progression is very rare. Failure after intravesical BCG in these patients is usually superficial and low-grade, and such patients can be managed with intravesical regimens including repeated BCG, BCG + cytokines, intravesical chemotherapy, hyperthermic chemotherapy, or novel immunotherapy. At the other end of the spectrum, failure to respond to BCG in high-risk T1 bladder cancer and / or carcinoma in situ is more problematic because those tumors are often likely to progress to muscle invasion. In these cases, radical cystectomy remains the last resort after BCG failure. Complete replacement of BCG with adjuvant therapy according to the present invention can be used in BCG-refractory NMIBC patients, i.e., patients for whom BCG therapy does not yield the desired therapeutic success.

[0097] Accordingly, in one embodiment, the present invention provides an adjuvant therapy for treating NMIBC in BCG-refractory patients, which comprises intravenous infusion of a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of the BCG-refractory patient, and the adjuvant therapy is not a photodynamic therapy method.

[0098] For patients with MIBC, the primary treatment is radical cystectomy, i.e., removal of the bladder and, if applicable, adjacent organs, i.e., the prostate and seminal vesicles in males, and the uterus and adnexa in females, including the incision of local lymph nodes. Cystectomy is also proposed for patients with NMIBC at high risk of progression, i.e., patients with multiple recurrent high-grade tumors or high-grade T1 tumors or high-grade tumors complicated with carcinoma in situ (CIS). Furthermore, cystectomy is proposed for patients with NMIBC who have received BCG immunotherapy but such treatment has failed. In patients scheduled for cystectomy, therapies according to the present invention may be performed as neoadjuvant therapy, i.e., prior to the primary treatment, which is cystectomy.

[0099] Therefore, in one embodiment, the therapy of the present invention is a neoadjuvant therapy for bladder cancer patients scheduled for cystectomy. Such patients are those for whom a cystectomy is to be performed, that is, those for whom a decision has already been made by a physician to undergo a procedure to remove the bladder within a predetermined relatively short period after the neoadjuvant therapy is administered. As understood, such patients are those for whom the cancer has already progressed to a stage where there is no other option but to perform a cystectomy. The patients may have either MIBC or NMIBC, which is at high risk of progression. In such patients, the standard treatment is cystectomy.

[0100] Therefore, in one embodiment, the therapy of the present invention is performed as neoadjuvant therapy for cystectomy, that is, in patients who require such treatment prior to such cystectomy, for example, patients diagnosed with MIBC.

[0101] Accordingly, in one embodiment, the present invention provides a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of neoadjuvant therapy for bladder cancer in a bladder cancer patient scheduled for cystectomy, the method comprising intravenous infusion of the composition into the patient's bladder, the neoadjuvant therapy being a method other than photodynamic therapy.

[0102] In another embodiment, the present invention provides a method of neoadjuvant therapy for bladder cancer in a patient with bladder cancer who is scheduled to undergo cystectomy, the method comprising intravenous infusion of a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the patient's bladder, the neoadjuvant therapy being a method other than photodynamic therapy.

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

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

[0105] The interval between the neoadjuvant therapy of the present invention and cystectomy may vary, but is preferably 0 to 6 weeks, for example 0 to 1, 2, 3, 4, 5, or 6 weeks, and more preferably 0 to 3 weeks, for example 1 or 2 weeks. "Zero" means that cystectomy is performed immediately after the neoadjuvant therapy according to the present invention.

[0106] Neoadjuvant therapy can be repeated before cystectomy. For example, it may be administered two or more times, such as three, four, five, six, seven, eight, nine, or ten times, or more than ten times. The interval between each treatment may be several days or several weeks, such as four days to four weeks, or one, two, or three weeks.

[0107] The neoadjuvant therapy of the present invention can be administered in combination with other neoadjuvant therapies, for example, before, simultaneously with, 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, barrubicin, adriamycin, mitomycin C, or combinations thereof, and neoadjuvant immunotherapy (intravesical infusion or systemic administration) of BCG.

[0108] After cystectomy, patients may receive systemic adjuvant chemotherapy using, for example, cisplatin, methotrexate, vinblastine, adriamycin, gemcitabine, doxorubicin, epirubicin, cyclophosphamide, or a combination thereof. Alternatively, or in addition, patients may receive systemic adjuvant immunotherapy using, for example, 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 International Publication Nos. 2010 / 077634, 2013 / 019906, and 2013 / 181452 (for anti-PD-L1 antibodies), and in International Publication Nos. 2004 / 004771, 2008 / 156712, 2009 / 114335, and 2013 / 079174 (for anti-PD-1 antibodies). All contents of these publications are incorporated herein by reference.

[0109] Adjuvant therapy or neoadjuvant therapy according to the present invention has several advantages compared to neoadjuvant radiotherapy, (neo)adjuvant chemotherapy, and (neo)adjuvant immunotherapy, which are known to have adverse effects such as nausea, vomiting, fatigue, anemia, epithelial surface damage, bowel discomfort / gastrointestinal stress, nephrotoxicity, neurotoxicity, swelling, immune system suppression, and infertility. In contrast, the most reported adverse reactions to HAL (in the form of Hexvix® / Cysview®) were transient and of mild to moderate intensity. The most frequently reported adverse reaction from clinical trials using Hexvix® / Cysview® was bladder spasm, reported in 2.4% of patients, voiding dysfunction in 1.8%, bladder pain in 1.7%, and hematuria in 1.7%.

[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, leading to the accumulation of porphyrins, particularly PpIX, the final intermediate in heme synthesis. Since such porphyrins are naturally occurring compounds in the body, there are "natural processes" in the body to break them down (metabolize) and excrete the resulting heme.

[0111] The present invention will be further explained by the following non-limiting embodiments. [Examples]

[0112] Example 1: Therapeutic efficacy of intravesical HAL infusion into the bladder of tumor-bearing rats method: Superficial bladder tumors were established in female Fischer rats weighing 150–175 g (purchased from Charles River Laboratories (Chatillon-sur-Chalronne, France)) using the rat bladder carcinoma cell line AY-27, as described in Francois et al., J.Urol.190(2), 2013, 731–736. The animals were used in the experiment 5 days after tumor cell inoculation.

[0113] Lyophilized HAL (in the form of Hexvix® powder) was dissolved in serum-free RPMI medium to a final concentration of 2 mg / mL (8 mM) immediately before intravenous infusion. The pH of the resulting solution was 6.8. 0.5 mL of the solution was intravenously infused into the bladder of rats, left in the bladder for approximately 1 hour, and then drained. The bladder was washed three times with PBS. HAL was not intravenously infused into the bladder of the control group of rats. Treatment was performed at normal body temperature.

[0114] Rats were sacrificed 12, 30, or 60 days after treatment by pentobarbital overdose. Bladder tissue was removed from the animals and transferred to a vial containing formaldehyde (4%) for at least 4 hours. The bladder was then cut into four sections and fixed for 48 hours. After different cycles of dehydration using ethanol and xylene gradients, the bladder tissue was embedded in paraffin. 5 μm paraffin-embedded sections were cut and stained with hematoxylin-eosin-saffron (HES) for histological evaluation.

[0115] result: The therapeutic efficacy at 12, 30, or 60 days after tumor inoculation was histologically determined as the degree of tumor regression. Rats were divided into four groups according to the degree of tumor regression. • No response (NR): Muscle-invasive tumor. • Moderate response ("MR"): A small number of tumor cells or several areas of an island of tumor cells. • Near complete response ("near CR"): A single island of tumor cells or isolated tumor cells. • Complete response (CR): No tumor cells present.

[0116] A good antitumor effect was defined as the sum of "near complete response" and "complete response."

[0117] The results are provided in Table 1, showing the therapeutic efficacy of treatment including intravesical infusion of HAL in rats with bladder cancer compared to a control group. Such treatment is performed in the absence of photoactivating light.

[0118] [Table 1]

[0119] Various embodiments of the present invention are as follows.

[0120] Embodiment 1: A method for treating bladder cancer, comprising the step of intravenously infusing a composition containing hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient, but not a method of photodynamic therapy.

[0121] Embodiment 2: The method according to Embodiment 1, wherein the method is performed using body temperature.

[0122] Embodiment 3: The method according to Embodiment 1 or 2, wherein the patient is human.

[0123] Embodiment 4: The method according to any one of Embodiments 1 to 3, wherein the method is carried out in the absence of photoactivating light.

[0124] Embodiment 5: The method according to Embodiment 4, wherein the photoactivating light is white light, blue light, red light, or any combination thereof.

[0125] Embodiment 6: The method according to any one of Embodiments 1 to 5, wherein the composition is intravenously administered into the patient's bladder through a catheter and left in the bladder for a period of about 10 minutes to about 3 hours.

[0126] Embodiment 7: The method according to any one of Embodiments 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 is the equivalent concentration of a pharmaceutically acceptable salt of HAL.

[0127] Embodiment 8: The method according to any one of Embodiments 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, more preferably a solution of HAL or a pharmaceutically acceptable salt thereof in a phosphate buffer.

[0128] Embodiment 9: The method according to Embodiment 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.

[0129] Embodiment 10: The method according to any one of Embodiments 1 to 9, wherein the composition is a solution of 2 mg / mL of HAL hydrochloride in an aqueous buffer containing disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide, and water.

[0130] Embodiment 11: The method according to any one of Embodiments 1 to 10, wherein the bladder cancer is muscle-invasive bladder cancer (MIBC).

[0131] Embodiment 12: The method according to any one of Embodiments 1 to 10, wherein the bladder cancer is non-muscle-invasive bladder cancer (NMIBC).

[0132] Embodiment 13: The method according to Embodiment 12, wherein the bladder cancer is NMIBC, which has a high risk of progression.

[0133] Embodiment 14: The method according to any one of Embodiments 1 to 13, wherein the method is performed on a bladder cancer patient who has undergone transurethral resection.

[0134] Embodiment 15: A method according to any one of Embodiments 1 to 14 for preventing the recurrence of the bladder cancer.

[0135] Embodiment 16: The method according to any one of Embodiments 1 to 13, wherein the method is adjuvant therapy, preferably the bladder cancer is NMIBC, and the method is performed before or after transurethral resection of NMIBC.

[0136] Embodiment 17: The method according to Embodiment 16, wherein the bladder cancer is NMIBC, and the method is performed after transurethral resection of NMIBC.

[0137] Embodiment 18: The method according to Embodiment 16 or 17, wherein the method replaces or partially replaces another adjuvant therapy for the treatment of bladder cancer, preferably the other adjuvant therapy being chemotherapy and / or immunotherapy, such as BCG treatment.

[0138] Embodiment 19: The method according to any one of Embodiments 1 to 13, wherein the method is neoadjuvant therapy, preferably the bladder cancer is MIBC, and the method is performed before cystectomy.

[0139] Embodiment 20: Use of hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment of bladder cancer, wherein the pharmaceutical is administered intravenously into the patient's bladder, and the treatment is not photodynamic therapy.

[0140] Embodiment 21: The use described in Embodiment 20, wherein the treatment is performed at body temperature.

[0141] Embodiment 22: The use according to Embodiment 20 or 21, wherein the patient is human.

[0142] Embodiment 23: The use according to any one of Embodiments 20 to 22, wherein the treatment is performed in the absence of photoactivating light.

[0143] Embodiment 24: The use described in Embodiment 23, wherein the photoactivating light is white light, blue light, red light, or any combination thereof.

[0144] Embodiment 25: The use according to any one of Embodiments 20 to 24, wherein the drug is intravenously administered into the patient's bladder through a catheter and left in the bladder for a period of approximately 10 minutes to approximately 3 hours.

[0145] Embodiment 26: The use according to any one of Embodiments 20 to 25, wherein the concentration of HAL in the pharmaceutical is in the range of 0.1 to 5% by weight based on the total weight of the pharmaceutical, or is the equivalent concentration of a pharmaceutically acceptable salt of HAL.

[0146] Embodiment 27: The use according to any one of Embodiments 20 to 26, wherein the pharmaceutical 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, more preferably a solution of HAL or a pharmaceutically acceptable salt thereof in a phosphate buffer.

[0147] Embodiment 28: The use described in Embodiment 27, wherein the pH of the pharmaceutical is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.2.

[0148] Embodiment 29: The use according to any one of Embodiments 20 to 28, wherein the pharmaceutical is a solution of 2 mg / mL of HAL hydrochloride in an aqueous buffer containing disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide, and water.

[0149] Embodiment 30: The use according to any one of Embodiments 20 to 29, wherein the bladder cancer is muscle-invasive bladder cancer (MIBC).

[0150] Embodiment 31: The use according to any one of Embodiments 20 to 29, wherein the bladder cancer is non-muscle-invasive bladder cancer (NMIBC).

[0151] Embodiment 32: The use according to Embodiment 31, wherein the bladder cancer is NMIBC, which has a high risk of progression.

[0152] Embodiment 33: The use according to any one of Embodiments 20 to 32, wherein the treatment is performed in a bladder cancer patient who has undergone transurethral resection.

[0153] Embodiment 34: The use according to any one of Embodiments 20 to 33, wherein the treatment is for the prevention of recurrence of the bladder cancer.

[0154] Embodiment 35: The use according to any one of Embodiments 20 to 32, wherein the treatment is adjuvant therapy, preferably the bladder cancer is NMIBC, and the treatment is performed before or after transurethral resection of NMIBC.

[0155] Embodiment 36: The use according to Embodiment 35, wherein the bladder cancer is NMIBC and the treatment is performed after transurethral resection of the NMIBC.

[0156] Embodiment 37: The use according to Embodiment 35 or 36, wherein the treatment replaces or partially replaces other adjuvant therapies for the treatment of bladder cancer, preferably the other adjuvant therapy being chemotherapy and / or immunotherapy, such as BCG therapy.

[0157] Embodiment 38: The use according to any one of Embodiments 20 to 32, wherein the treatment is neoadjuvant therapy, preferably the bladder cancer is MIBC, and the treatment is performed before cystectomy.

Claims

1. A composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating bladder cancer, wherein the method comprises intravenous infusion of the composition into the bladder of a patient, and the method is not a method of photodynamic therapy.

2. The composition for use according to claim 1, wherein the method described above is carried out at body temperature.

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

4. The composition for use according to any one of claims 1 to 3, wherein the therapeutic method is carried out in the absence of photoactivating light.

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

6. The composition for use according to any one of claims 1 to 5, wherein the composition is intravenously administered into the bladder of the patient through a catheter and left in the bladder for a period of about 10 minutes to about 3 hours.

7. The composition for use according to any one of claims 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 is the equivalent concentration of a pharmaceutically acceptable salt of HAL.

8. The composition for use according to any one of claims 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, more preferably a solution of HAL or a pharmaceutically acceptable salt thereof in a phosphate buffer.

9. The composition for use 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 for use according to any one of claims 1 to 9, wherein the composition is a solution of 2 mg / mL of HAL hydrochloride in an aqueous buffer containing disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide, and water.

11. The composition for use according to any one of claims 1 to 10, wherein the bladder cancer is muscle-invasive bladder cancer (MIBC).

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

13. The composition for use according to claim 12, wherein the bladder cancer is NMIBC, which has a high risk of progression.

14. The composition for use according to any one of claims 1 to 13, wherein the method of the aforementioned therapy is performed in a bladder cancer patient who has undergone transurethral resection.

15. A composition for use according to any one of claims 1 to 14 in preventing the recurrence of bladder cancer.

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

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

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

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

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