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WO2024184417A1 - Thérapie contre le cancer de la vessie - Google Patents

Thérapie contre le cancer de la vessie Download PDF

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Publication number
WO2024184417A1
WO2024184417A1 PCT/EP2024/055897 EP2024055897W WO2024184417A1 WO 2024184417 A1 WO2024184417 A1 WO 2024184417A1 EP 2024055897 W EP2024055897 W EP 2024055897W WO 2024184417 A1 WO2024184417 A1 WO 2024184417A1
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WO
WIPO (PCT)
Prior art keywords
composition
therapy
bladder cancer
bladder
hal
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PCT/EP2024/055897
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English (en)
Inventor
Gry Stensrud
Aslak Godal
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Photocure Asa
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Application filed by Photocure Asa filed Critical Photocure Asa
Publication of WO2024184417A1 publication Critical patent/WO2024184417A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • This invention relates to a therapy for bladder cancer. More particularly, it relates to a therapy for bladder cancer in which hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, is instilled into a patient’s bladder without carrying out photodynamic therapy (PDT).
  • HAL hexyl 5-ALA ester
  • PDT photodynamic therapy
  • Such therapy finds use as a therapeutic treatment for bladder cancer and as a prophylactic treatment to prevent its recurrence. It may be used as a stand-alone therapy, or as an adjuvant or neoadjuvant therapy in combination with other therapies and/or surgical procedures, such as radiotherapy, chemotherapy, immunotherapy, transurethral resection (TUR), or a radical cystectomy.
  • therapies and/or surgical procedures such as radiotherapy, chemotherapy, immunotherapy, transurethral resection (TUR), or a radical cystectomy.
  • Bladder cancer is the ninth most common cancer diagnosis worldwide, with more than 330,000 new cases each year and more than 130,000 deaths per year. At any point in time, 2.7 million people have a history of urinary bladder cancer.
  • bladder cancer ultimately depends on cystoscopic examination of the bladder (cystoscopy) and histological evaluation of the resected tissue.
  • cystoscopic examination of the bladder cystoscopic examination of the bladder (cystoscopy)
  • 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% as muscle invasive bladder cancer (MIBC).
  • NMIBC non-muscle invasive bladder cancer
  • MIBC muscle invasive bladder cancer
  • TUR transurethral resection
  • Cystectomy is also advocated in patients with NMIBC who are at high risk of progression, i.e. patients having multiple recurrent high-grade tumors or highgrade T1 tumors, or high-grade tumors with concurrent carcinoma-in-situ (CIS). Further, cystectomy is advocated in patients with NMIBC who have received Bacillus Calmette-Guerin (BCG) immunotherapy but where such treatment has failed.
  • BCG Bacillus Calmette-Guerin
  • neoadjuvant therapies i.e. therapies prior to the main treatment which is the cystectomy
  • neoadjuvant chemotherapy is used.
  • Neoadjuvant radiotherapy With neoadjuvant radiotherapy, down staging of the cancer after radiotherapy takes about 4-6 weeks. However, a delay of surgery in patients with locally advanced bladder cancer beyond 90 days has shown to cause a significant increase in extravesical disease (81 vs. 52%). Neoadjuvant radiotherapy is not recommended according to the current European guidelines on MIBC since no data exist to support that neoadjuvant radiotherapy for operable MIBC increases survival.
  • Neoadjuvant chemotherapy has many advantages including that chemotherapy is delivered at the earliest time-point, when the burden of micrometastatic disease is expected to be low; that tolerability of chemotherapy is expected to be better before cystectomy rather than after; and that, hypothetically, patients with micrometastatic disease might respond to neoadjuvant therapy and reveal favorable pathological status determined mainly by negative lymph node status and negative surgical margins.
  • Neoadjuvant cisplatin-containing chemotherapy has been shown to significantly improve survival (5% absolute improvement in survival at 5 years).
  • delayed cystectomy may compromise the outcome in patients who are not sensitive to chemotherapy and, generally, pre-operative anemia and neuropathy is more common in patients receiving neoadjuvant chemotherapy prior to cystectomy.
  • neoadjuvant chemotherapy has its limitations regarding patient selection, current development of surgical technique, and current chemotherapy combinations.”
  • neoadjuvant therapies for bladder cancer patients who are scheduled for a cystectomy, i.e. bladder cancer patients diagnosed with MIBC or NMIBC who are at high risk of progression, including multiple recurrent high-grade tumors or high-grade T1 tumors or highgrade tumors with concurrent carcinoma-in-situ (CIS).
  • the standard treatment is resection of the tumor by TUR.
  • Instillation into the bladder of a composition comprising HAL, or a pharmaceutically acceptable salt thereof, and exposing the inside of the bladder to blue light may be used to improve visualization of bladder cancer during cystoscopy and/or TUR.
  • cystoscopy and TUR are performed using white light.
  • photodynamic diagnosis/detection is often used in such procedures.
  • PDD involves the administration of a photosensitizer or a precursor thereof (which collectively may be referred to herein as a "photosensitizing agent”) to an area of interest.
  • the photosensitizer or precursor thereof is taken up into the cells, where a precursor of a photosensitizer is converted into a photosensitizer.
  • the photosensitizer Upon exposure of the area of interest to light of a suitable wavelength, the photosensitizer is activated (i.e. excited) and, upon relaxation to its ground state, fluorescence occurs and is detected.
  • Hexyl 5-ALA ester hexaminolevulinate, HAL
  • HAL preferably penetrates rapidly proliferating cells, e.g. tumor cells, where it is converted into porphyrins (e.g. protoporphyrin IX, “PpIX”), which are photosensitizers.
  • porphyrins e.g. protoporphyrin IX, “PpIX”
  • PpIX protoporphyrin IX
  • the porphyrins Upon blue-light activation, the porphyrins are activated and, upon relaxation to their ground state, emit red light and thus enable specific and accurate visualization of the tumor.
  • Hexvix® Photocure ASA, Norway
  • Cysview® is a commercially available approved drug that comprises HAL and is used in PDD in cystoscopy and TUR procedures.
  • HAL-guided cystoscopy and TUR has increased detection of both papillary tumors and flat carcinoma-in-situ (CIS) lesions, the latter of which are difficult to detect with white light alone.
  • HAL-guided TUR of bladder cancer in patients with NMIBC has further reduced the rate of residual tumors after such procedures and has led to superior recurrence free survival (RFS) rates and prolonged RFS intervals compared to white light TUR alone (see Rink M, et al. Eur Urol 4(64), 2013, 624).
  • a TaT1 tumor can be completely resected by HAL-guided TUR, and HAL- guided TUR favorably affects recurrence rate, these tumors may recur and progress to muscle invasive bladder cancer in a limited number of cases. It is therefore necessary to consider adjuvant therapy, i.e. adjuvant chemotherapy or adjuvant chemotherapy and adjuvant immunotherapy, in all patients. The choice of therapy may be considered differently according to what risk is acceptable for the individual patient. Usually, a patient will receive one immediate, post-TUR instillation of chemotherapy into the bladder. The need for further adjuvant intravesical therapy depends on the patients’ prognosis.
  • a single immediate instillation reduces the risk of recurrence and is considered as the standard treatment, i.e. no further treatment is given in these patients before recurrence.
  • a single immediate instillation remains an incomplete treatment because the likelihood of recurrence and/or progression is considerable.
  • mitomycin C mitomycin C
  • epirubicin epirubicin
  • doxorubicin doxorubicin
  • BCG Bacillus Calmette-Guerin
  • Photodynamic therapy has also been suggested for the treatment of bladder cancer and clinical studies have been carried out to investigate efficacy and safety of such treatment.
  • PDT involves the administration of a photosensitizing agent to an area of interest followed by activation of the photosensitizer by light of a suitable wavelength to elicit a PDT effect (i.e. photoactivating light).
  • the therapeutic effect of PDT is based on a phototoxic reaction: the photosensitizing agent is taken up into the cells where, if the agent is a precursor of a photosensitizer, the precursor is converted into a photosensitizer.
  • the photosensitizer is activated, i.e.
  • HAL and its salts have been suggested for use in PDT of bladder cancer (see for instance US 2005/0031541, Example 21). HAL and its salts have also been proposed for use in PDT for bladder cancer in which HAL is instilled into the bladder of a patient and the inside of the bladder is exposed to blue light (see WO 2017/103285 and US 2019/0022404), for use in a neoadjuvant therapy for bladder cancer in a patient scheduled for a cystectomy in which HAL is instilled into the patient’s bladder and the inside of the bladder is exposed to light (WO 2017/103283 and US 2018/0369379), and for use in therapy of bladder cancer in which a combination of HAL and anti-PD-L1 and/or anti-PD-1 -antibodies is instilled into the bladder of a patient and the inside of the bladder is exposed to light (WO 2017/103280).
  • Example 21 of US 2015/0191419 dark toxicity of HAL is determined in WiDr cells derived from a primary adenocarcinoma of the rectosigmoid colon. HAL is added to the cell culture medium in concentrations of 0.001 to 1 mM. A weak cell toxicity is observed in the range of 0.3 to 1 mM with a minimum cell survival rate of 85%, i.e. only 15% or less were killed. Neither Saleh Al-Omari nor US 2015/0191419 reports any investigation of the dark toxicity of HAL in a bladder cancer cell line. Studies carried out in cell lines in vitro, i.e. on isolated tumor cells, differ from the reality in a patient (e.g.
  • US 2013/0158293 relates to enhancers for cancer thermotherapy comprising 5-ALA and 5-ALA derivatives.
  • Thermotherapy is a treatment method which takes advantage of the fact that cancer cells are heat-sensitive compared to normal cells and thus inhibits proliferation of the cancer cells.
  • 5-ALA is shown to exhibit an anti-cancer effect in various cell lines in the absence of photodynamic therapy, i.e. without light illumination.
  • HAL hexyl 5-ALA ester
  • the therapy described herein may be combined with other methods of treatment for bladder cancer, including surgical procedures, chemotherapy and/or immunotherapy.
  • its use as an adjuvant or neoadjuvant therapy in the management of bladder cancer is also proposed. Since the therapy is performed in the absence of photoactivating light, it addresses the problems associated with conventional methods of PDT in which the delivery of light inside the patient’s bladder may be complicated and cumbersome, and which require the use of specially designed equipment to carry out the PDT.
  • the use of HAL or its pharmaceutically acceptable salts without photoactivating light is expected to be well tolerated by patients with minimal side effects.
  • the invention thus provides a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, for use in a method of therapy for bladder cancer, wherein said method comprises instillation of said composition into the bladder of a patient, and wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • the invention provides a method of therapy for bladder cancer, said method comprising the step of instillation into the bladder of a patient a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, and wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • the term “photodynamic therapy” or “PDT” refers to a treatment involving the combined use of: (i) a photosensitizing agent; and (ii) photoactivating light, i.e. light of an appropriate wavelength to activate the photosensitizer and convert it into a therapeutically active form.
  • the photosensitizing agent may be a photosensitizer or it may be a precursor of a photosensitizer. In some cases, the photosensitizing agent is a precursor of a photosensitizer that may be administered to the patient and is converted in vivo to a photosensitizer.
  • Hexyl 5-ALA ester is an example of a precursor of the photosensitizer protoporphyrin IX (“PpIX”).
  • PDT involves administration of the photosensitizing agent to the treatment area which is then exposed to photoactivating light.
  • the photosensitizer is therapeutically inactive until it is exposed to photoactivating light. It is only after exposure to photoactivating light (i.e. “photoactivation”) that the photosensitizer is converted into a therapeutically active form.
  • Light which is capable of activating the photosensitizer and converting it into 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 will vary depending on the photosensitizer. In order to achieve the desired photoactivation and thus the intended therapeutic effect, the light must be provided at a certain dose (i.e. the light dose), and at a suitable, defined wavelength and fluence rate.
  • cancer refers to cells undergoing abnormal proliferation. Growth of such cells typically causes the formation of a tumor.
  • tumor refers to an abnormal mass of tissue containing cancerous cells. Cancerous cells may be benign, pre-malignant or malignant. Such cells may be invasive and/or have the ability to metastasize to other locations in the body.
  • cancer includes cancerous growths, tumors, and their metastases.
  • metastatic cancer 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 may break away from a primary tumor, enter the lymphatic and blood systems and circulate to other parts of the body (e.g. to normal tissues). Here they may settle and grow within the normal tissues. When tumor cells metastasize, the new tumors may be referred to as metastatic cancer.
  • bladder cancer refers to cancer that arises from the tissues of the bladder.
  • Bladder cancer is classified by the extent of spread of the cancer (i.e. staged) and graded based on how abnormal and aggressive the cells appear under the microscope. Staging is usually performed with transurethral resection of the bladder tumor (TUR) and radiologic imaging (e.g. CT or MRI).
  • TUR transurethral resection of the bladder tumor
  • CT radiologic imaging
  • Papillary tumors confined to the mucosa or which invade the lamina basement are classified as Ta or T1.
  • Flat lesions that do not invade the basement membrane of the bladder mucosa are termed Tis (in situ). All three categories (Tis, Ta and T1) are grouped together as non-muscular invasive disease for therapeutic purposes, i.e. as non-muscle invasive bladder cancer (NMIBC).
  • NMIBC non-muscle invasive bladder cancer
  • Tumors in the remaining categories T2, T3 and T4 are termed muscular-invasive disease,
  • treatment refers to the reduction, alleviation or elimination, of a disease. It includes palliative treatment, i.e. treatment intended to minimise, or partially or completely inhibit the development of the disease.
  • the disease is bladder cancer.
  • prevention refers to absolute prevention, i.e. maintenance of normal levels with reference to the extent or appearance of a particular symptom of the disease, or to reduction or alleviation of the extent or timing (e.g. delaying) of the onset of that symptom.
  • a pharmaceutical composition is meant a composition in any form suitable to be used for a medical purpose.
  • a “therapeutically effective amount” relates to an amount that will lead to the desired therapeutic effect, i.e. a therapeutic or prophylactic amount of an agent which is effective to achieve its intended purpose. Such an amount may be provided by a single administration or by multiple (e.g. repeated) administration of any of the agents described herein. For example, several dosages of the agents described herein may need to be administered to make up the “therapeutically effective amount” that will lead to the desired therapeutic effect. While individual patient needs may vary, determination of optimal ranges for effective amounts of the agents herein described is within the capability of one skilled in the art. Generally, the dosage regimen for treating a disease with any of the agents described herein may be selected by those skilled in the art in accordance with a variety of factors including the extent and severity of the disease.
  • the term “patient” refers to a human subject under the treatment of a clinician.
  • hexyl 5-ALA ester denotes n-hexyl aminolevulinate, i.e. n-hexyl 5-amino-4-oxo-pentanoate.
  • pharmaceutically acceptable salt denotes a salt that is suitable for and fulfils the requirements related to for instance safety, bioavailability and tolerability (see for instance P. H. Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002).
  • adjuvant therapy refers to the administration of a therapeutic or prophylactic agent in addition to the main treatment for the disease.
  • the term “neoadjuvant therapy” refers to the administration of a therapeutic or prophylactic agent before (i.e. prior to) to the main treatment for the disease.
  • the therapy for bladder cancer according to the invention is not a method of photodynamic therapy, i.e. it does not rely on the activation of the photosensitizer by photoactivating light. It may alternatively be referred to as “non-photodynamic”.
  • the therapy herein described relies on the effect of HAL or its pharmaceutically acceptable salts in the absence of photoactivating light.
  • the therapy does not involve the delivery of photoactivating light to the inside of the patient’s bladder subsequent to intravesical (i.e. inside the bladder) administration of HAL or one of its pharmaceutically acceptable salts.
  • composition for use in the invention is able to suppress or delay tumor growth and/or prevent recurrence of tumors in a patient’s bladder without the need to carry out photodynamic therapy to achieve this therapeutic effect.
  • the composition is used in a method which does not involve the use of photoactivating light capable of producing a therapeutically active form of the photosensitizer PpIX in vivo.
  • Wavelengths of light that are generally considered suitable to produce a therapeutically active form of the photosensitizer PpIX in vivo following the administration of HAL or a pharmaceutically acceptable salt thereof include: white light, i.e. visible light having wavelengths of from about 350 to about 700 nm; blue light, i.e. light having a wavelength of from about 360 to about 450 nm; and red light, i.e. light having a wavelength of from about 600 to about 670 nm.
  • the method of therapy according to the invention is performed without exposing the inside of the patient’s bladder to white light, blue light or red light, or any combination thereof in which two or more wavelengths of light are used either simultaneously (i.e. at the same time) or sequentially (i.e.
  • Light doses that are given during irradiation of the inside of the bladder with white and/or red and/or blue light during PDT may vary. Typically, these may be in the range from 0.01 to 100 J/cm 2 . Fluence rates that are used during irradiation of the inside of the bladder with white and/or red and/or blue light during PDT may vary. Duration of light exposure in conventional methods of PDT will vary. Typically, the light may be provided for a period of about 10 to 30 minutes.
  • the therapy for bladder cancer according to the invention is performed without the application of heat, i.e. it is not a method of thermotherapy in which the patient’s bladder is subjected to heating.
  • the therapy is carried out at body temperature, for example at a temperature in the range of from about 35°C to about 38°C, e.g. from about 36°C to about 37°C.
  • composition comprising HAL, or a pharmaceutically acceptable salt thereof, for use in the invention is instilled into the patient’s bladder, preferably through a catheter.
  • the composition is retained in the bladder for a predetermined period of time.
  • the patient’s bladder will preferably be empty at the time of instillation and, if necessary, may be evacuated prior to instillation of the composition.
  • the composition may be retained in the bladder for a predetermined period of time.
  • a suitable period of time may readily be determined by those skilled in the art.
  • the composition may, for example, be left in the bladder for a period of from about 10 minutes to about 3 hours, preferably from about 20 minutes to about 2 hours, more preferably from about 30 minutes to 1 hour.
  • the composition may be retained in the patient’s bladder for no less than about 30 minutes or no less than about 1 hour.
  • the bladder is evacuated. If the patient cannot retain the composition for a suitable period of time, for example for about 10 minutes, or for about 20 minutes, or for about 30 minutes, or for about 1 hour, the instillation procedure may be repeated.
  • the composition is instilled into the patient’s bladder through a catheter and is left in the bladder for about 30 minutes or for about 1 hour. The bladder is then evacuated.
  • the composition for use in the invention comprises hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof.
  • HAL hexyl 5-ALA ester
  • the synthesis of hexyl 5-ALA ester is known in the art. It may, for example, be prepared as described in WO 96/28412, the entire contents of which are incorporated herein by reference.
  • hexyl 5-ALA ester may be prepared by reaction of 5-ALA with hexanol in the presence of a catalyst, such as an acid.
  • hexyl 5-ALA ester hydrochloride is commercially available, e.g. in the form of Hexvix® (available from Photocure ASA, for example) or Cysview® (available from Photocure Inc., for example).
  • the hexyl 5-ALA ester for use in the invention may be employed in the form of a pharmaceutically acceptable salt.
  • Such salts are preferably acid addition salts with pharmaceutically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric, nitric, hydrobromic, phosphoric, sulfuric, sulfonic acid and sulfonic acid derivatives.
  • Suitable acids include, for example, hydrochloric, nitric, hydrobromic, phosphoric, sulfuric, 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.
  • a preferred acid addition salt of HAL for use in the invention is the hydrochloride salt. Synthetic procedures for salt formation are conventional in the art and are for instance described in WO 2005/092838.
  • the composition will contain HAL or a pharmaceutically acceptable salt in a therapeutically effective amount.
  • concentrations can readily be 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%, and most preferably 0.17%, which corresponds to e.g. 0.2% HAL hydrochloride (8 mM).
  • composition for use in the invention is a pharmaceutical composition and may comprise pharmaceutically acceptable carriers or excipients, such as stabilizers.
  • the composition is preferably a liquid composition, more preferably a suspension or even more preferably a solution of HAL in a liquid carrier.
  • Preferred liquid carriers include water and aqueous solutions, for example aqueous buffers.
  • the composition for use in the invention is an aqueous solution of HAL or a pharmaceutically acceptable salt thereof.
  • the composition for use in the invention is a solution of HAL, or a pharmaceutically acceptable salt thereof, in an aqueous buffer such as an aqueous phosphate buffer.
  • an aqueous phosphate buffer comprising disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.
  • the composition for use in the invention is an aqueous solution of HAL hydrochloride.
  • the composition may be a solution of HAL hydrochloride in an aqueous buffer.
  • composition for use in the invention is a liquid composition comprising water
  • pH of said composition is preferably in the range of 4.5 to 7.5, more preferably in the range of 5.7 to 7.2.
  • HAL or the pharmaceutically acceptable salt thereof is provided in a lyophilized form, and is reconstituted in a liquid carrier, preferably in water or an aqueous solution, most preferably in an aqueous buffer, prior to use.
  • the composition for use of the invention is Hexvix®, i.e. a solution of HAL hydrochloride (2 mg/ml; 8 mM) in an aqueous buffer comprising disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.
  • Hexvix® i.e. a solution of HAL hydrochloride (2 mg/ml; 8 mM) in an aqueous buffer comprising disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.
  • the composition for instillation into the patient’s bladder is a solution comprising 2 mg/ml HAL hydrochloride.
  • the composition for use in the invention may further comprise anti-PD-L1 antibodies and/or anti-PD-1 antibodies.
  • Anti-PD-L1 is a monoclonal antibody designed to interfere with a protein called PD-L1 (programmed deathligand 1).
  • Anti-PD-L1 targets PD-L1 expressed on cancer cells and tumorinfiltrating 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 the activation of T cells, 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 death receptor-1) protein, which is present at high levels in many cancer types, e.g. bladder cancer. By competitively blocking the interaction with PD-1 receptors, it is believed that anti- PD-1 thereby restores anti-cancer T-cell responses.
  • anti-PD-L1 antibodies and anti-PD-1 antibodies target different components of the same interaction mechanism between immune cells (specifically killer T cells) and cancer cells, but have a similar therapeutic effect: anti-PD-L1 antibodies target PD-L1 expressed on cancer cells while anti-PD-1 antibodies target the other half of this mechanism, i.e. PD-1), which is expressed on killer T cells.
  • the anti-PD-L1 antibodies and anti-PD-1 antibodies referred to herein act to inhibit PD-L1 and PD- 1 , respectively. Accordingly, these may also be referred to as antagonizing anti- PD-L1 antibodies and antagonizing anti-PD-1 antibodies.
  • the invention thus provides a composition for use in a method of therapy for bladder cancer, wherein said composition comprises: (i) hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof; and (ii) anti-PD-L1 antibodies and/or anti-PD-1 antibodies, and said method comprises instillation of said composition into the bladder of a patient, and further wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • anti-PD-L1 antibodies and/or anti-PD-1 antibodies said method comprises instillation of said composition into the bladder of a patient, and further wherein said method is not a method of photodynamic therapy.
  • the invention provides a method of therapy for bladder cancer, said method comprising the step of instillation into the bladder of a patient a composition comprising: (i) hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof; and (ii) anti-PD-L1 antibodies and/or anti-PD-1 antibodies, and wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • anti-PD-L1 antibodies and/or anti-PD-1 antibodies and wherein said method is not a method of photodynamic therapy.
  • Preferred anti-PD-L1 antibodies for use in the invention are those by Roche, preferably MPDL3280A. Such anti-PD-L1 antibodies are described in
  • Preferred anti-PD-1 antibodies for use in the invention are those by Merck, preferably 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.
  • anti-PD-1 antibodies that find use in the invention are those by Bristol-Myers Squibb, preferably nivolumab (Opdivo). Such anti-PD-1 antibodies are described in WO 2004/004771 , the entire content of which is incorporated herein by reference.
  • composition for use in the invention additionally comprises anti-PD-L1 antibodies and/or anti-PD-1 antibodies
  • these will be present in a therapeutically effective amount.
  • the precise amount will depend on various factors such as the chosen anti-PD-L1 antibodies and/or anti-PD-1 antibodies, whether the therapy is intended for the treatment and/or prevention of bladder cancer, if the therapy is a stand-alone therapy or is intended to be carried out as an adjuvant or neoadjuvant therapy in combination with other therapies and/or surgical procedures such as those herein described, etc.
  • a therapeutically effective amount of the anti-PD-L1 antibodies and/or anti-PD-1 antibodies can readily be determined by those skilled in the art taking account of such factors.
  • the method of therapy for bladder cancer according to the invention can be used in the treatment of bladder cancer.
  • the composition is administered to a patient in need thereof, i.e. a patient diagnosed with bladder cancer.
  • the bladder cancer may be non-muscular invasive bladder cancer (NMIBC), or muscular invasive bladder cancer (MIBC).
  • the bladder cancer is MIBC in which the cancer has entered the muscle layer of the bladder.
  • the bladder cancer is NMIBC in which the cancer has not entered the muscle layer of the bladder. This cancer appears as papillary tumors and flat lesions (carcinoma-in-situ, CIS).
  • the bladder cancer is NMIBC with a high risk of progression, for example including multiple recurrent high-grade tumors or high-grade T1 tumors or high-grade tumors with concurrent carcinoma-in-situ (CIS).
  • a high risk of progression for example including multiple recurrent high-grade tumors or high-grade T1 tumors or high-grade tumors with concurrent carcinoma-in-situ (CIS).
  • the therapy according to the invention may be carried out once, or repeatedly, depending on the extent and aggression of the cancer. For example, it may be carried out 2 or more times, e.g. 3, 4, 5, 6, 7, 8, 9 or 10 times, with a period between the treatments. In some cases, it may be carried out more than 10 times. The period between treatments may vary, but may for example range from about 4 days to 4 weeks, e.g., it may be 1 , 2 or 3 weeks.
  • the therapy according to the invention is carried out repeatedly in the form of an induction therapy followed by a maintenance therapy.
  • the induction therapy comprises carrying out the method of therapy according to the invention 2 or more times, e.g.
  • the induction therapy may comprise carrying out the method of therapy according to the invention once a week for a period of about 6 weeks.
  • the maintenance therapy comprises carrying out the method of therapy according to the invention once a week for a period of 2, 3 or 4 weeks. Such maintenance therapy may be performed once, twice, three or 4 times a year.
  • the method of therapy for bladder cancer according to the invention can be used as a stand-alone bladder cancer treatment.
  • it can be used as an adjuvant therapy in the treatment of bladder cancer, i.e. in addition to a primary (i.e. main) therapy for bladder cancer.
  • the invention thus 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, wherein said method comprises instillation of said composition into the bladder of a patient, and wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • the invention provides a method of adjuvant therapy for bladder cancer, said method comprising the instillation into the bladder of a patient a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • the adjuvant therapy according to the invention can be carried out prior to, simultaneously, or after the main treatment for the disease (i.e. bladder cancer).
  • the main treatment for the bladder cancer will be dependent on the patient’s diagnosis, for example whether they have been diagnosed with NMIBC or with MIBC.
  • the main treatment for such patients will typically be a transurethral resection (TUR), i.e. a procedure in which a cystoscope is used to visualize the inside of the bladder through the urethra in order to detect and identify tumors and lesions and to resect such tumors and lesions.
  • TUR transurethral resection
  • the adjuvant therapy according to the invention may be carried out either prior to or after TUR, or it may be carried out both prior to and after TUR.
  • the invention thus 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, wherein said method comprises instillation of said composition into the bladder of a bladder cancer patient, wherein said patient has undergone TUR and/or will undergo TUR, and wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5- ALA ester
  • the invention provides a method of adjuvant therapy for bladder cancer in a bladder cancer patient who has undergone TUR and/or will undergo TUR, said method comprising the instillation into the bladder of said patient a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • the method of therapy of the invention is carried out as an adjuvant therapy to TUR in patients in need of such treatment, i.e. patients who are diagnosed with NMIBC or patients who are suspected of having NMIBC.
  • the adjuvant therapy of the invention may be carried out subsequent to a TUR.
  • the adjuvant therapy for treating NMIBC will comprise instillation into the bladder of a patient having undergone TUR of a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof.
  • the adjuvant therapy of the invention is carried out directly after the TUR.
  • the adjuvant therapy of the invention is carried out as a separate procedure after the TUR, for example after some days, weeks or months following the TUR procedure.
  • the adjuvant therapy of the invention may be carried out after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or more, or after 1 , 2, 3, 4 or 5 weeks or more, or after 1 , 2, 3, 4, 5 or 6 months.
  • the adjuvant therapy of the invention may be carried out prior to a TUR.
  • the adjuvant therapy for treating a patient who is suspected of having NMIBC will comprise instillation into the bladder of such a patient a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof.
  • HAL hexyl 5-ALA ester
  • the adjuvant therapy of the invention is carried out directly prior to the TUR.
  • the adjuvant therapy of the invention is carried out as a separate procedure prior to the TUR, for example some days, weeks or months prior to the TUR procedure.
  • the adjuvant therapy of the invention may be carried out 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or more, or 1 , 2, 3, 4 or 5 weeks or more, or 1 , 2, 3, 4, 5 or 6 months prior to the TUR.
  • Any conventional TUR procedure for the treatment of NMIBC or suspected NMIBC may be used as the main treatment.
  • Such a procedure may involve photodynamic detection of lesions in the bladder, for example using HAL or a pharmaceutically acceptable salt thereof with blue light.
  • the TUR procedure typically comprises the use of a cystoscope and exposure of the inside of the patient’s bladder to white light from the cystoscope for a visual inspection to detect and identify lesions, followed by resection of said lesions.
  • the TUR procedure may involve the photodynamic detection (PDD) of lesions.
  • the TUR procedure may comprise: a) instillation of a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient; b) exposing the inside of said bladder to white light for a visual inspection followed by exposing said inside of the bladder to blue light for fluorescence detection of lesions; c) exposing the bladder to white light for resection of said lesions; and d) optionally monitoring the completeness of the resection by exposing said inside of the bladder again to blue light for fluorescence detection of residual lesions.
  • HAL hexyl 5-ALA ester
  • the invention thus provides a composition comprising hexyl 5- ALA ester (HAL), or a pharmaceutically acceptable salt thereof, for use in a method of treating NMIBC by carrying out a transurethral resection of NMIBC and, subsequently, carrying out an adjuvant therapy comprising instillation of said composition into the bladder, wherein said adjuvant therapy is not a method of photodynamic therapy.
  • HAL hexyl 5- ALA ester
  • the invention provides a method of treating NMIBC in a patient in need thereof, said method comprising carrying out a transurethral resection of NMIBC and, subsequently, carrying out an adjuvant therapy comprising instillation into the bladder of said patient a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, wherein said adjuvant therapy is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • the 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, said method comprising carrying out an adjuvant therapy comprising instillation of said composition into the bladder of said patient, wherein said adjuvant therapy is not a method of photodynamic therapy, and subsequently carrying out a transurethral resection of NMIBC.
  • HAL hexyl 5-ALA ester
  • the invention provides a method of treating a patient suspected of having NMIBC, said method comprising carrying out an adjuvant therapy comprising instillation into the bladder of said patient a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, wherein said adjuvant therapy is not a method of photodynamic therapy, and subsequently carrying out a transurethral resection of NMIBC.
  • an adjuvant therapy comprising instillation into the bladder of said patient a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, wherein said adjuvant therapy is not a method of photodynamic therapy, and subsequently carrying out a transurethral resection of NMIBC.
  • HAL hexyl 5-ALA ester
  • the 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 or diagnosed with NMIBC, said method comprising: a) carrying out an adjuvant therapy comprising instillation of said composition into the bladder of said patient, wherein said adjuvant therapy is not a method of photodynamic therapy; b) subsequently carrying out a transurethral resection of NMIBC; and c) subsequently carrying out a further adjuvant therapy according to step a).
  • HAL hexyl 5-ALA ester
  • the adjuvant therapy for NMIBC or suspected NMIBC according to the invention may be carried out once or repeatedly. For example, it may be carried out 2 or more times, e.g. 3, 4, 5, 6, 7, 8, 9 or 10 times, or more than 10 times, with a period between each treatment of several days or weeks, e.g. 4 days to 4 weeks, or 1 , 2 or 3 weeks.
  • the therapy according to the invention may alternatively be used as an adjuvant therapy in the treatment of bladder cancer in combination with radiotherapy, chemotherapy and/or immunotherapy treatments.
  • the therapy for treating NMIBC of the invention can be used in combination with chemotherapy, e.g. systemic or intravesical administration of suitable chemotherapeutic agents for NMIBC, such as cisplatin, methotrexate, vinblastine, valrubicin, adriamycin or mitomycin C and/or in combination with suitable immunotherapeutic agents for NMIBC, such as systemic administration of anticancer vaccines or intravesical administration of Bacillus Calmette-Guerin (BCG).
  • suitable chemotherapeutic agents for NMIBC such as cisplatin, methotrexate, vinblastine, valrubicin, adriamycin or mitomycin C
  • suitable immunotherapeutic agents for NMIBC such as systemic administration of anticancer vaccines or intravesical administration of Bacillus Calmette-Guerin (BCG).
  • the adjuvant therapy for treating NMIBC according to the invention may replace or partially replace other adjuvant therapies like chemotherapy and/or immunotherapy.
  • the adjuvant therapy according to the invention replaces or partially replaces other adjuvant therapies which are intravesically administered, e.g. mitomycin and/or BCG.
  • the adjuvant therapy for treating NMIBC according to the invention partially or fully replaces BCG.
  • BCG treatment is usually started a few weeks after a transurethral resection of NMIBC and is given once a week for 6 weeks, optionally followed by a maintenance period in which it is given, e.g. once a week for three weeks at the three-, six- and 12-month marks.
  • the adjuvant therapy according to the invention may replace 1, 2, 3, 4, 5 or all 6 of such BCG treatments and/or the maintenance BCG treatments.
  • the invention thus provides an adjuvant therapy for treating NMIBC in BCG refractory patients, comprising instillation of a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a BCG refractory patient, wherein said adjuvant therapy is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • cystectomy i.e. removal of the bladder and, if applicable, adjacent organs, i.e. prostate and seminal vesicles in men, and uterus and adnexa in women, including the dissection of regional lymph nodes.
  • Cystectomy is also advocated in patients with NMIBC who are at high risk of progression, i.e. patients having multiple recurrent high-grade tumors or highgrade T1 tumors or high-grade tumors with concurrent carcinoma-in-situ (CIS).
  • cystectomy is advocated in patients with NMIBC who have received BCG immunotherapy but where such treatment has failed.
  • the therapy according to the invention may be carried out as a neoadjuvant therapy, i.e. prior to the main treatment which is a cystectomy.
  • the therapy of the invention is thus a neoadjuvant therapy for a bladder cancer patient who is scheduled for a cystectomy.
  • a patient is one for whom a decision has already been taken by a physician that a cystectomy will be performed, i.e. the patient will undergo a procedure to remove the bladder within a pre-determined and relatively short period of time from carrying out the neoadjuvant therapy.
  • a patient is one in whom the cancer has already advanced to a stage where there is no alternative but to carry out a cystectomy.
  • the patient may either have MIBC or they may have NMIBC which is at high risk of progression.
  • the standard treatment will be a cystectomy.
  • the therapy of the invention is carried out as a neoadjuvant therapy to cystectomy, i.e. prior to such a cystectomy, in a patient who is in need of such treatment, for example a patient who has been diagnosed with MIBC.
  • the invention thus 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 who is scheduled for a cystectomy, said method comprising instillation of the composition into the bladder of said patient, and wherein said neoadjuvant therapy is not a method of photodynamic therapy.
  • HAL hexyl 5- ALA ester
  • the invention provides a method of neoadjuvant therapy for bladder cancer in a bladder cancer patient who is scheduled for a cystectomy, said method comprising instillation into the bladder of said patient a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof, and wherein said neoadjuvant therapy is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • the 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, said method comprising: a) neoadjuvant therapy in which said composition is instilled into the bladder of said patient and wherein said neoadjuvant therapy is not a method of photodynamic therapy; and b) carrying out a cystectomy.
  • HAL hexyl 5-ALA ester
  • the invention provides a method of treating MIBC in a patient, said method comprising: a) neoadjuvant therapy in which a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof is instilled into the bladder of said patient and wherein said neoadjuvant therapy is not a method of photodynamic therapy; and b) carrying out a cystectomy.
  • a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof is instilled into the bladder of said patient and wherein said neoadjuvant therapy is not a method of photodynamic therapy; and b) carrying out a cystectomy.
  • HAL hexyl 5-ALA ester
  • the time period between the neoadjuvant therapy of the invention and the cystectomy may vary but is preferably zero to 6 weeks, e.g. zero to 1 , 2, 3, 4, 5 or 6 weeks, more preferably zero to 3 weeks, e.g. 1 or 2 weeks. “Zero” means that the cystectomy is carried out directly after the neoadjuvant therapy according to the invention.
  • the neoadjuvant therapy can be carried out repeatedly prior to the cystectomy. For example, it may be carried out 2 or more times, e.g. 3, 4, 5, 6, 7, 8, 9 or 10 times, or more than 10 times.
  • the period between each treatment may be several days or weeks, e.g. 4 days to 4 weeks, or 1 , 2 or 3 weeks.
  • neoadjuvant therapy of the invention can be carried out in combination with other neoadjuvant therapies, for example prior to, simultaneously, or after other neoadjuvant therapies, such as neoadjuvant radiotherapy, neoadjuvant chemotherapy, and neoadjuvant immunotherapy.
  • neoadjuvant therapies include neoadjuvant chemotherapy (intravesical instillation or systemic administration) of cisplatin, methotrexate, vinblastine, valurubicin, adriamycin, mitomycin C, or combinations thereof, and neoadjuvant immunotherapy (intravesical instillation or systemic administration) of BCG.
  • the patient may receive systemic adjuvant chemotherapy with e.g. cisplatin, methotrexate, vinblastine, adriamycin, gemcitabine, doxorubicin, epirubicin, cyclophosphamide or combinations thereof.
  • systemic adjuvant immunotherapy with e.g. anti- PD-L1 antibodies and/or anti-PD-1 antibodies.
  • Suitable anti-PD-L1 antibodies and/or anti-PD-1 antibodies include those as herein described in respect of the composition for use in the invention.
  • Formulations suitable for parenteral e.g.
  • the adjuvant or neoadjuvant therapies according to the method of the invention have several advantages compared to neoadjuvant radiotherapy, (neo)adjuvant chemotherapy and (neo)adjuvant immunotherapy, where nausea, vomiting, fatigue, anemia, damage to epithelial surfaces, intestinal discomfort/gastrointestinal stress, nephrotoxicity, neurotoxicity, swelling, depression of the immune system and infertility are well-known and common adverse effects.
  • nausea, vomiting, fatigue, anemia, damage to epithelial surfaces, intestinal discomfort/gastrointestinal stress, nephrotoxicity, neurotoxicity, swelling, depression of the immune system and infertility are well-known and common adverse effects.
  • HAL in the form of HexvixO/Cysview®
  • HAL has a highly favorable metabolic profile compared to chemotherapeutics, e.g. cisplatin. HAL interferes with the body’s own heme biosynthetic pathway and leads of accumulation of porphyrins, particularly PpIX which is the last intermediate in heme synthesis. Since such porphyrins are compounds which naturally occur in the body, there is a “natural process” in the body for degrading (metabolizing) and excreting degraded heme.
  • Example 1 Therapeutic efficacy of intravesical HAL instillation into the bladder of tumor-bearing rats
  • the rat bladder carcinoma cell line AY-27 was used to establish superficial bladder tumors in Female Fischer rats (purchased from Charles River Laboratories, Chatillon-sur-Chalronne, France) weighing 150-175 g as described in Frangois et al., J. Urol. 190(2), 2013, 731-736. The animals were used in the experiments 5 days after tumor cell inoculation.
  • Lyophilized HAL in the form of Hexvix® powder was dissolved in RPMI medium without serum to a final concentration of 2 mg/ml (8 mM) immediately before instillation. pH of the resulting solution was 6.8. 0.5 ml of the solution was instilled into the rat bladder, left in the bladder for about 1 hour and then evacuated. The bladder was washed three times with PBS. No HAL was instilled into bladders of the rats in the control groups. The treatments were performed at normal body temperature. The rats were sacrificed 12, 30 or 60 days after treatment by an overdose of pentobarbital. Bladders were removed from the animals and transferred into vials with formaldehyde (4%) for a minimum of 4 hours.
  • the bladder was cut into 4 parts and fixed for 48 hours. Following different cycles of dehydration with gradients of ethanol and xylene, the bladder tissue was embedded into paraffin. Paraffin embedded sections of 5 pm were cut and stained with haematoxylin-eosin- safran (HES) for histology assessment.
  • HES haematoxylin-eosin- safran
  • NR muscle-invasive tumor.
  • MR Moderate response
  • Near complete response (“Near CR”): singular islet of tumor cells or isolated tumor cells.
  • a good anti-tumor effect was defined as the sum of “Near CR” and “CR”.
  • Results are provided in Table 1 , showing the therapeutic efficacy of a treatment comprising the bladder instillation of HAL into rats having bladder cancer compared to a control group, wherein such treatment is performed in the absence of photoactivating light: Table 1
  • Embodiment 1 A method of therapy for bladder cancer, said method comprising the step of instillation into the bladder of a patient a composition comprising hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, and wherein said method is not a method of photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • Embodiment 2 The method according to Embodiment 1 , wherein said method is carried out at body temperature.
  • Embodiment 3 The method according to Embodiment 1 or 2, wherein said patient is a human.
  • Embodiment 4 The method according to any one of Embodiments 1 to 3, wherein said method is performed in the absence of photoactivating light.
  • Embodiment 5 The method according to Embodiment 4, wherein said photoactivating light is white light, blue light, red light or any combination thereof.
  • Embodiment 6 The method according to any one of Embodiments 1 to 5, wherein said composition is instilled into the bladder of the patient through a catheter and is left in the bladder for a period of from about 10 minutes to about 3 hours.
  • 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 from 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.
  • Embodiment 8 The method according to any one of Embodiments 1 to 7, wherein said 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.
  • said 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.
  • Embodiment 9 The method according to Embodiment 8, wherein the pH of said composition is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.2.
  • Embodiment 10 The method according to any one of Embodiments 1 to 9, wherein said composition is a solution of 2 mg/ml HAL hydrochloride in an aqueous buffer comprising disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.
  • Embodiment 11 The method according to any one of Embodiments 1 to 10, wherein said bladder cancer is muscular invasive bladder cancer (MIBC).
  • MIBC muscular invasive bladder cancer
  • Embodiment 12 The method according to any one of Embodiments 1 to 10, wherein said bladder cancer is non-muscular invasive bladder cancer (NMIBC).
  • NMIBC non-muscular invasive bladder cancer
  • Embodiment 13 The method according to Embodiment 12, wherein said bladder cancer is NMIBC with a high risk of progression.
  • Embodiment 14 The method according to any one of Embodiments 1 to 13, wherein said method is carried out in a bladder cancer patient who has undergone a transurethral resection.
  • Embodiment 15 The method according to any one of Embodiments 1 to 14 for the prevention of recurrence of said bladder cancer.
  • Embodiment 16 The method according to any one of Embodiments 1 to 13, wherein said method is an adjuvant therapy, preferably wherein said bladder cancer is NMIBC and said method is carried out prior to or after a transurethral resection of NMIBC.
  • Embodiment 17 The method according to Embodiment 16, wherein said bladder cancer is NMIBC and said method is carried out after a transurethral resection of NMIBC.
  • Embodiment 18 The method according to Embodiment 16 or 17, wherein said method replaces or partially replaces other adjuvant therapies for the treatment of bladder cancer, preferably wherein said other adjuvant therapies are chemotherapy and/or immunotherapy, for example BCG treatment.
  • said other adjuvant therapies are chemotherapy and/or immunotherapy, for example BCG treatment.
  • Embodiment 19 The method according to any one of Embodiments 1 to 13, wherein said method is a neoadjuvant therapy, preferably wherein said bladder cancer is MIBC and said method is carried out prior to a cystectomy.
  • Embodiment 20 Use of hexyl 5-ALA ester (HAL), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of bladder cancer, wherein said medicament is instilled into the bladder of a patient, and wherein said treatment is not photodynamic therapy.
  • HAL hexyl 5-ALA ester
  • Embodiment 21 Use according to Embodiment 20, wherein said treatment is carried out at body temperature.
  • Embodiment 22 Use according to Embodiment 20 or 21 , wherein said patient is a human.
  • Embodiment 23 Use according to any one of Embodiments 20 to 22, wherein said treatment is performed in the absence of photoactivating light.
  • Embodiment 24 Use according to Embodiment 23, wherein said photoactivating light is white light, blue light, red light or any combination thereof.
  • Embodiment 25 Use according to any one of Embodiments 20 to 24, wherein said medicament is instilled into the bladder of the patient through a catheter and is left in the bladder for a period of from about 10 minutes to about 3 hours.
  • Embodiment 26 Use according to any one of Embodiments 20 to 25, wherein the concentration of HAL in the medicament is in the range from 0.1 to 5% by weight based on the total weight of the medicament, or the equivalent concentration of a pharmaceutically acceptable salt of HAL.
  • Embodiment 27 Use according to any one of Embodiments 20 to 26, wherein said medicament 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.
  • Embodiment 28 Use according to Embodiment 27, wherein the pH of said medicament is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.2.
  • Embodiment 29 Use according to any one of Embodiments 20 to 28, wherein said medicament is a solution of 2 mg/ml HAL hydrochloride in an aqueous buffer comprising disodium phosphate dihydrate, potassium dihydrogen phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.
  • Embodiment 30 Use according to any one of Embodiments 20 to 29, wherein said bladder cancer is muscular invasive bladder cancer (MIBC).
  • MIBC muscular invasive bladder cancer
  • Embodiment 31 Use according to any one of Embodiments 20 to 29, wherein said bladder cancer is non-muscular invasive bladder cancer (NMIBC).
  • NMIBC non-muscular invasive bladder cancer
  • Embodiment 32 Use according to Embodiment 31, wherein said bladder cancer is NMIBC with a high risk of progression.
  • Embodiment 33 Use according to any one of Embodiments 20 to 32, wherein said treatment is carried out in a bladder cancer patient who has undergone a transurethral resection.
  • Embodiment 34 Use according to any one of Embodiments 20 to 33, wherein said treatment is for the prevention of recurrence of said bladder cancer.
  • Embodiment 35 Use according to any one of Embodiments 20 to 32 wherein said treatment is an adjuvant therapy, preferably wherein said bladder cancer is NMIBC and said treatment is carried out prior to or after a transurethral resection of NMIBC.
  • Embodiment 36 Use according to Embodiment 35, wherein said bladder cancer is NMIBC and said treatment is carried out after a transurethral resection of NMIBC.
  • Embodiment 37 Use according to Embodiment 35 or 36, wherein said treatment replaces or partially replaces other adjuvant therapies for the treatment of bladder cancer, preferably wherein said other adjuvant therapies are chemotherapy and/or immunotherapy, for example BCG treatment.
  • said other adjuvant therapies are chemotherapy and/or immunotherapy, for example BCG treatment.
  • Embodiment 38 Use according to any one of Embodiments 20 to 32, wherein said treatment is a neoadjuvant therapy, preferably wherein said bladder cancer is MIBC and said treatment is carried out prior to a cystectomy.

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Abstract

La présente invention concerne le traitement du cancer de la vessie. En particulier, l'invention concerne une composition comprenant un ester d'hexyle 5-ALA (HAL), ou un sel pharmaceutiquement acceptable de celui-ci, destinée à être utilisée dans une méthode de traitement du cancer de la vessie, ladite méthode comprenant l'instillation de ladite composition dans la vessie d'un patient, et ladite méthode n'étant pas une méthode de thérapie photodynamique.
PCT/EP2024/055897 2023-03-07 2024-03-06 Thérapie contre le cancer de la vessie WO2024184417A1 (fr)

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