Treatment methods for lower urothelial carcinoma

Abstract

This provides a method for treating lower urothelial carcinoma. [Solution] The present invention provides methods, devices, and kits for the treatment of urothelial carcinoma of the lower urinary tract using an antimetabolite (e.g., gemcitabine). In some embodiments, these methods, devices, and kits relate to the treatment of urothelial carcinoma of the lower urinary tract using antimetabolites (e.g., gemcitabine) and immunomodulatory agents. Local administration of antimetabolites such as gemcitabine to the bladder can result in multiple biological effects, including modulating the immune response in the tumor microenvironment, inducing systemic immunity and antigen presentation, and inducing cytotoxicity.

Description

Technical Field

[0001] Cross - References to Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 62 / 333,151, filed on May 6, 2016, and U.S. Provisional Application No. 62 / 443,614, filed on January 6, 2017. The entire contents of each of these applications are hereby incorporated by reference into this specification.

Background Art

[0002] Background of the Invention Bladder cancer is a significant medical problem, and currently available treatment options are unsatisfactory for many reasons. Generally, bladder cancer is classified as muscle - invasive bladder cancer (MIBC) or non - muscle - invasive bladder cancer (NMIBC). The pathological classification and staging of bladder cancer are as follows: pTa (urothelial involvement); pTis (high - risk urothelial carcinoma in situ); pT1 (lamina propria invasion); pT2 (muscle invasion); pT3 (perivesical fat invasion); and pT4 (invasion of pelvic organs). Bladder cancer can also be graded as grade 1 / 3 (well - differentiated); grade 2 / 3 (moderately differentiated); grade 3 / 3 (poorly differentiated). Additionally, bladder cancer can be staged as stage 0 - IV. Most bladder cancers are transitional cell carcinomas of epithelial origin and are classified as non - muscle - invasive cancers (NMIBC) confined to the inner layer of the bladder. At the time of initial presentation, most bladder cancers are superficial NMIBC, which includes diseases at stages pTa, pTis, and pT1. MIBC includes stages pT2, pT3, and pT4.

[0003] A typical clinical protocol for early-stage NMIBC involves visualization by cystoscopy, Subsequent transurethral resection (TUR) is a known surgical removal of tumors (one or more). However, the recurrence rate after surgery is high, and the cancer can progress to muscle-invasive disease. Therefore, Surgery helps prevent or delay the incidence and severity of recurrence. Adjuvant for cystic therapy or immunotherapy agents intravesically Intravesical infusion (chemotherapy administered into the bladder via a urinary catheter) It is often used in combination with direct delivery of the drug. Calmette-Guérin bacilli (BCG) Such immunotherapy drugs are typically injected into the bladder after surgery. However, many Many patients do not respond to BCG, and BCG treatment also induces various adverse effects. This can lead to an interruption of treatment. Chemotherapy agents are usually reserved for patients who have failed BCG treatment. Chemotherapy is typically administered in the bladder to concentrate the chemotherapy agent at the tumor site. It is administered internally, avoiding systemic exposure to the drug while eliminating any residual tumor after resection.

[0004] One such chemotherapy agent used in clinical trials to treat bladder cancer is G It is mucitabine. Gemcitabine (2',2'-difluorodeoxycytidine) is metastatic Gemcitabine is a pyrimidine analog that has activity against bladder cancer. Weekly bladder infusions treat superficial bladder cancer and NMIBC. It has also been used in clinical trials for the purpose of [details omitted]. Gemcitabine is typically, typically A maximum dose of 500-2000 mg in 100 mL of saline solution, administered over 1-2 hours. It is injected once or twice a week for several weeks.

[0005] These liquid formulations are released from the bladder after a short dwell time of 1-2 hours. Since they are excreted, it is well known that their therapeutic benefits are limited. Furthermore, high concentrations (40 mg / mL) and high doses (up to 2 grams per infusion) control the residence time. It is used in attempts to overcome limitations and achieve therapeutic tissue levels. However, intravesical (intravesical) delivery of high doses of gemcitabine results in significant systemic absorption. It can cause gastrointestinal, bladder, and myelotoxicity, and in addition to local tolerability issues, clinical Further limiting its usefulness.

[0006] Therefore, improved treatment for urothelial carcinoma of the lower urinary tract A different approach is still needed.

[0007] Published applications US2012 / 0203203, US2013 / 0158675, US 2015 / 0360012, US20150165177, US2015 / 016517 8, US20160199544, WO2014 / 145638, WO20152007 52, WO2011 / 031855, are incorporated herein by reference in their entirety. All other references disclosed herein are incorporated in their entirety by reference. Born. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent Application Publication No. 2012 / 0203203 Specification [Patent Document 2] U.S. Patent Application Publication No. 2013 / 0158675 [Patent Document 3] U.S. Patent Application Publication No. 2015 / 0360012 [Patent Document 4] U.S. Patent Application Publication No. 2015 / 0165177 [Patent Document 5] U.S. Patent Application Publication No. 2015 / 0165178 [Patent Document 6] U.S. Patent Application Publication No. 2016 / 0199544 [Patent Document 7] International Publication No. 2014 / 145638 [Patent Document 8] International Publication No. 2015 / 200752 [Patent Document 9] International Publication No. 2011 / 031855 [Summary of the Invention] [Means for Solving the Problems]

[0009] Brief Summary of the Invention[[ID=3*]] Local administration of antimetabolites such as gemcitabine to the bladder modulates the immune response in the tumor microenvironment, induces systemic immunity and antigen presentation, and induces cytotoxicity and other multiple biological effects. Therefore, the present application discloses a method for treating urothelial carcinoma of the lower urinary tract, comprising the step of locally administering an effective amount of an antimetabolite to the bladder of an individual.

[0010] In some embodiments, this method is a method for enhancing the immune response against urothelial carcinoma of the lower urinary tract of an individual, comprising the step of administering an effective amount of an antimetabolite to the individual, and the antimetabolite is locally delivered to the bladder.

[0011] ​​In some embodiments, this method is used to treat recurrent or progressive urothelial carcinoma of the lower urinary tract in individuals. A method for reducing row size, comprising the step of administering an effective amount of an antimetabolite to an individual, The method includes delivering an antimetabolite locally to the bladder.

[0012] In some embodiments, this method is used to improve cancer immunity in individuals with urothelial carcinoma of the lower urinary tract. A method for improving the tumor microenvironment for epidemic therapy, comprising administering an effective amount of an antimetabolite to the individual. The method includes a step of administering an antimetabolite, wherein the antimetabolite is delivered locally to the bladder.

[0013] In some embodiments, this method involves treating individuals with urothelial carcinoma of the lower urinary tract with radiotherapy. A method for sensitizing an individual, comprising the step of administering an effective amount of an antimetabolite to the individual. The method includes delivering an antimetabolite locally to the bladder.

[0014] In some embodiments following any of the above methods, this method is used to treat muscle-infiltrating bladder in individuals. A method for treating bladder cancer, comprising a step of locally delivering an effective dose of gemcitabine to the bladder. The method involves gemcitabine being delivered continuously for at least 24 hours, including the use of p. include.

[0015] In some embodiments following any of the above methods, this method is used for bladder preservation in individuals. A method comprising the step of locally delivering an effective amount of gemcitabine to the bladder, The method includes delivering the Tabin continuously for at least 24 hours.

[0016] In some embodiments following any of the above methods, this method is used to achieve non-muscle infiltration in individuals. A method for treating bladder cancer, comprising the step of locally delivering gemcitabine to the bladder. The method includes delivering gemcitabine continuously over a period of at least 24 hours.

[0017] In some embodiments following any of the above methods, the antimetabolite is a nucleoside analyte. It may be. In some of these embodiments, the antimetabolite is gemcitabine. In some embodiments following any of the methods, the antimetabolite is administered for at least about 24 hours. Over time, it is continuously delivered into the bladder. In some embodiments following any of the above methods The antimetabolite is delivered in a first dose at the first stage of delivery, and thereafter, It is delivered in a second dose at the second time. In some embodiments, the first time and the second The second period is continuous. Alternatively, in some embodiments, the first and second periods are rest periods. They can be separated by the duration of the medication.

[0018] In some embodiments following any of the above methods, the antimetabolite is administered in a dose of approximately 1 mg / day to approximately 3 mg / day. It is delivered in a dose of 00 mg / day. In some embodiments following any of the above methods, in urine The concentration of the antimetabolite is approximately 0.1 μg / mL to approximately 200 μg / mL during the delivery period. In some of these embodiments following any of the above methods, the concentration of antimetabolites in the urine is The concentration is approximately 10 μg / mL during the delivery period. In some embodiments following any of the above methods, the concentration is approximately 10 μg / mL. The concentration of antimetabolites in the plasma of an individual is less than approximately 1 μg / mL. In some embodiments following the above, the concentration of the antimetabolite is less than approximately 0.1 μg / mL. In some embodiments following any of the above methods, during the delivery of antimetabolites, the urine of the individual The ratio of antimetabolites in the body to antimetabolites in plasma is greater than approximately 500:1.

[0019] In some embodiments following any of the above methods, the antimetabolite is used for at least one month. The delivery period for each antimetabolite is at least one day, and the delivery of each antimetabolite is at least one day. The interval between delivery periods is approximately one week or less. In some embodiments following any of the above methods, The interval between each antimetabolite period is 14 days. In some embodiments, each antimetabolite There is no interval between delivery periods.

[0020] In some embodiments, this method ensures that a) the concentration of an antagonist in the individual's urine is at least a) the duration of delivery of the first antimetabolite, which is approximately 0.1 μg / mL; b) the drug-free period; and c) the individual The concentration of antimetabolites in the body's urine was at least approximately over at least a portion of the drug-free period. This includes a second antimetabolite delivery period of 0.1 μg / mL. In some embodiments, urine The concentration of the antimetabolite in the drug remained at approximately 1.0 μg / m³ for at least half of the drug-free period. It's higher than L.

[0021] In some embodiments following any of the above methods, this method provides an effective amount of a second drug to an individual The further step includes administering to the body. In some embodiments following any of the above methods, Drug 2 is delivered at the time when antimetabolite delivery is initiated. In some embodiments, The second drug is delivered before the antimetabolite is delivered. In some embodiments, the second drug The agent is delivered after the delivery of the antimetabolite has begun. In further embodiments, the second These drugs are delivered after the delivery of antimetabolites has been terminated.

[0022] In some embodiments following any of the above methods, the antimetabolite delivery period and the second drug delivery The delivery periods may overlap. In some embodiments, the delivery period of the antimetabolite and the second drug The drug delivery period may not overlap.

[0023] In some embodiments following any of the above methods, the second drug is delivered systemically. In some embodiments, the second drug is delivered locally. In some embodiments, the second drug is the During the first period of drug delivery 2, the drug is delivered systemically, followed by the second period of drug delivery. Local delivery in the second phase follows. In some embodiments, the second drug is the second drug It is delivered locally during the first period of drug delivery, and then during the second period of the second drug delivery. Systemic delivery continues during this period. In some embodiments, the first time of the second drug delivery period The first phase and the second phase of the second drug delivery period are separated by at least approximately one month.

[0024] In some embodiments following any of the above methods, the antimetabolite and the second agent are the same It is delivered at times. In some of these embodiments, the antimetabolite and the second agent are single It is delivered via a delivery device. In some embodiments following any of the above methods, alternative The antagonist and the second agent are delivered at the same release rate. In other embodiments, the metabolic antagonists are also delivered. The antisubstance and the second agent are delivered at different release rates.

[0025] In some embodiments, the second drug is delivered separately from the antimetabolite.

[0026] In some embodiments following any of the above methods, the second drug is delivered systemically. In some embodiments, the second drug is delivered locally.

[0027] In some embodiments following any of the above methods, the second agent is a chemotherapeutic agent. In some embodiments following any of the methods, the chemotherapeutic agent is paclitaxel, docetaxel The following are selected from the group consisting of chloroform, carboplatin, cisplatin, and oxaliplatin. In some embodiments, the second agent is an immunomodulatory agent. The inhibitory agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint The inhibitors include PD-L1, CTLA4, PD-L2, PD-1, B7-H3, and B7-H3. 4. HVEM, B and T lymphocyte attenuators (BTLA), killer inhibitor receptors (K IR), GAL9, TIM3, A2AR, LAG-3, phosphatidylserine, CD27 If you're using TNF-α, CD33, Siglec-5, Siglec-7, or Siglec-9... Inhibition of immune checkpoint proteins selected from the group consisting of Siglec-11 and others. It is a harmful agent. In some embodiments, the immunomodulatory agent is an agonist of a co-stimulatory immune molecule. In some embodiments, the co-stimulatory immune molecules are CD40, OX40, ICOS, and CD28. CD137 / 4-1BB, CD27, IL-10, TGF-beta, TOR receptor and Selected from the group consisting of glucocorticoid-inducible TNFR-related protein GITR. .

[0028] In some embodiments following any of the above methods, the individual does not receive radiation therapy. In one embodiment, the method further includes radiotherapy.

[0029] In some embodiments following any of the above methods, the antimetabolite is a neoadjuvant. They are delivered under certain conditions. In some embodiments, the antimetabolite is delivered under adjuvant conditions. In some embodiments following any of the above methods, the antimetabolite is delivered in the preoperative treatment. In some embodiments, the antimetabolite is delivered during perioperative procedures.

[0030] In some embodiments following any of the above methods, the method provides a third treatment including surgery. Furthermore, in some of these embodiments, the delivery of antimetabolites to the individual is at the time of surgery. It may be initiated by... In some embodiments following any of the above methods, an antimetabolite is introduced into the organism. The delivery is initiated during the cystoscopy. In some embodiments following any of the above methods, The delivery of antimetabolites to the individual is initiated during the preoperative cystoscopy. In this state, the delivery of antimetabolites to the individual is initiated during postoperative cystoscopy.

[0031] In some embodiments following any of the above methods, the antimetabolite is administered into the bladder cavity (inside the bladder). The device delivers the contents into the bladder. One of these embodiments according to any of the above methods. In this department, intravesical (intravesical) devices are designed for intravesical (intravesical) insertion. The housing contains a dosage form including worms and an antimetabolite, and the housing holds the dosage form. It is configured to release an antimetabolite in an amount effective for treating urothelial carcinoma. In some embodiments of the law, intravesical (intravesical) drug delivery devices are metabolized. It contains an antagonist, releases it in a controllable manner, and retains the device in the individual's bladder. The retaining shape configured and the deployment shape for the device to pass through the urethra of the individual Includes a housing that is elastically deformable between and . A part according to any of the above devices. In this embodiment, the device has a drug reservoir lumen with a first wall and a second wall as boundaries. It includes, the first wall is impermeable to the drug, and the second wall is permeable to the drug. Yes. In some embodiments according to any of the above devices, the first wall and the second wall are mutual Adjacent to and together with the above, it forms an annular tube that defines the lumen of the drug reservoir. In some embodiments according to any of the described devices, the second wall has a length of the structure of the first wall. It is in the form of a strip extending at least in part. In some embodiments, the first wall is cylindrical. Yes. In some embodiments, the second wall is disk-shaped. In some embodiments, An intravesical (intravesical) drug delivery device includes at least two drug reservoir lumens.

[0032] In some embodiments following any of the above methods, an antimetabolite is delivered by Deby When used, antimetabolites are released from the device by osmosis. In this embodiment, the antimetabolite is released from the device by diffusion.

[0033] In some embodiments according to any of the above devices, metabolic antagonists are included in the housing. The substance is in a non-liquid form. In some of these embodiments, the non-liquid form is a tablet, granules, The material is selected from the group consisting of semi-solids, powders, capsules, and combinations thereof.

[0034] In some embodiments following any of the above methods, the method provided herein involves lower urine A method for treating urothelial carcinoma of the urothelial carcinoma, wherein the urothelial carcinoma is bladder cancer, comprising the method. In some embodiments, bladder cancer is locally advanced bladder cancer or metastatic bladder cancer. In some embodiments, bladder cancer is muscle-invasive bladder cancer. In some embodiments, bladder Bladder cancer is non-muscle-invasive bladder cancer. In some embodiments following any of the above methods, bladder Bladder cancer is carcinoma in situ. In some embodiments, bladder cancer is treated with BCG (Calmette Gerrit). It is refractory cancer or papillary bladder cancer (caused by bacilli). In this context, bladder cancer is a BCG-unresponsive cancer.

[0035] In some embodiments following any of the above methods, this method provides an effective amount of an antimetabolite. The procedure includes a step of administering the substance to an individual, where the individual is a human. Some practices follow one of the above methods. In terms of administration methods, the individual is unsuitable for systemic treatment. Partial implementation following one of the above methods Morphologically, the individual has a damaged immune system. Some implementations follow any of the above methods. In this state, the individual has high levels of immune checkpoint proteins. Therefore, the individual has low levels of immune checkpoint proteins. In some embodiments that follow the same principle, the organism has a high level of nucleoside transporters. In the embodiment, the organism has a lower level of nucleoside transporter.

[0036] In some embodiments following any of the above methods, the antimetabolite is gemcitabine. The method further includes the step of determining the gemcitabine / metabolite ratio in the urine, below a threshold. The ratio indicates an effective treatment.

[0037] In some embodiments, the following is performed on an individual, comprising a) an antimetabolite and b) a second agent. A kit for treating urothelial carcinoma of the urinary tract, wherein an antimetabolite is applied locally to the bladder. Kits, which are in a device for delivery, are provided herein. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the second agent is immune It is a regulator.

[0038] A device for local delivery of an antimetabolite and a second drug to the bladder of an individual. A device comprising a) an antimetabolite and b) a second drug is also provided herein. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the second This drug is an immunomodulator.

[0039] In some embodiments of the above devices, intravesical (intravesical) drug delivery devices The chair is a housing that defines the reservoir; the first unit contained within the reservoir is That is, a first unit containing an antagonist; and a lyza in a position separate from the first unit. A second unit contained within the housing, which releases the drug in vivo from the housing. The unit includes a second unit containing a functional agent that promotes release. In some embodiments, the functional agent This is a penetrant, drug solubilizer, or a combination thereof, and the housing contains a reservoir and flow It includes at least one drug release opening connected to the body. [Brief explanation of the drawing]

[0040] [Figure 1] Figure 1 shows tumor size, determined by the mean solid intensity compared to controls, in rats treated with 90 μg / ml, 180 μg / ml, or 350 μg / ml gemcitabine.

[0041] [Figure 2] Figure 2 shows gemcitabine levels in bladder tissue after one week of continuous delivery of gemcitabine.

[0042] [Figure 3]Figure 3 shows gemcitabine levels in rat bladder tissue layers after sustained delivery of gemcitabine.

[0043] [Figure 4] Figure 4 shows the levels of activated and regulatory T cells present in the tumor microenvironment after perfusion with 90–180 μg / mL gemcitabine.

[0044] [Figure 5] Figure 5 shows the percentage of activated CD8+ and CD4+ cells in the spleen of untreated control rats and rats treated with gemcitabine.

[0045] [Figure 6] Figure 6 shows TGF-β levels in untreated control rats and rats treated with 180 μg / mL gemcitabine.

[0046] [Figure 7] Figure 7 shows IL-10 levels in untreated control rats and rats treated with 180 μg / mL gemcitabine.

[0047] [Figure 8] Figures 8A–8C illustrate intravesical (intravesical) devices that can be used to provide localized and sustained delivery of antimetabolites. Figure 8A is a plan view. Figure 8B is a cross section taken along line 3–3 in Figure 8A. Figure 8C is a diagram of one end portion of the device positioned within the working channel of a deployment apparatus, partially shown in cross section.

[0048] [Figure 9] Figure 9 shows that similar levels of gemcitabine were excreted in the urine in the miniature pig study and the human Phase IB clinical trial.

[0049] [Figure 10]Figure 10 shows that urinary gemcitabine (dFdC) and metabolite (dFdU) concentrations were similar in the miniature pig study and the human Phase IB study. [Modes for carrying out the invention]

[0050] This application relates to the local delivery of antimetabolites (e.g., gemcitabine) to the bladder. This application provides a novel method for treating urothelial carcinoma of the urinary tract (e.g., bladder cancer). Local delivery of gemcitabine using specific drug regimens is effective in the immune environment of the tumor microenvironment. It modulates responses, induces systemic immunity and antigen presentation, and induces cytotoxicity. This is partly based on the surprising finding that it produces multiple biological effects, such as inducing certain behaviors. When delivered locally to the bladder using a drug regimen, gemcitabine penetrates deep into the bladder tissue. Even after penetration and cessation of delivery, it can persist in the urine for an extended period. Even more surprisingly, it was found that the bladder, as described herein, Local delivery of antimetabolites is particularly effective when combined with a second drug (e.g., an immunomodulator). When used in this way, it is useful for treating urothelial carcinoma of the lower urinary tract.

[0051] Therefore, in various embodiments, the present invention provides for the treatment of urothelial carcinoma of the lower urinary tract in individuals. Methods to enhance the immune response against urothelial carcinoma of the lower urinary tract in individuals, Methods to reduce recurrence or progression of urothelial carcinoma of the urinary tract, tumor microscopy for cancer immunotherapy Methods to improve the environment, sensitizing individuals with urothelial carcinoma of the lower urinary tract for radiation therapy. A method comprising the step of administering an effective amount of an antimetabolite to an individual, wherein the antimetabolite This provides a method for local delivery to the bladder. In some embodiments, this method is the The method further includes the delivery of two drugs, for example, immunomodulatory drugs. In some embodiments, the individual Systemic administration is unsuitable, or the patient is immunocompromised.

[0052] In another embodiment, a lower urinary tract in an individual comprising a) an antimetabolite and b) a second agent. A kit for treating urothelial carcinoma, in which gemcitabine antimetabolite is used in the bladder. A kit is provided, which is in a device for local delivery. In another embodiment, a substitute for the bladder. A device for local delivery of an antimetabolite and a second drug, comprising: a) antimetabolite and b) a device comprising a second drug is provided. In some embodiments, an antimetabolite The first agent is gemcitabine. In some embodiments, the second agent is an immunomodulator. I. Method of the present invention

[0053] This application relates, in some embodiments, to a method for treating urothelial carcinoma of the lower urinary tract in an individual. There is an effective amount of an antimetabolite (e.g., nucleoside analogs, e.g., gemcitabine). The step includes delivering an antimetabolite (e.g., a nucleoside analog, e.g.) to an individual, and includes the step of delivering an antimetabolite (e.g., a nucleoside analog, e.g.) For example, gemcitabine is delivered locally to the bladder, providing a method. Therefore, a method for enhancing the immune response against urothelial carcinoma of the lower urinary tract in an individual, The effective amount of an antimetabolite (e.g., nucleoside analog, e.g., gemcitabine) is applied to the organism. The process includes a step of delivering an antimetabolite (e.g., a nucleoside analog, e.g., gem A method is provided in which cytabine is delivered locally to the bladder. In some embodiments, A method for reducing the recurrence or progression of urothelial carcinoma of the lower urinary tract, comprising an effective amount of an antimetabolite. Stem cells that deliver antisubstances (e.g., nucleoside analogs, e.g., gemcitabine) to an individual It contains antimetabolites (e.g., nucleoside analogs, e.g., gemcitabine) A method is provided for local delivery to the bladder. In some embodiments, the urinary tract of the lower urinary tract A method for improving the tumor microenvironment for cancer immunotherapy in individuals with epithelial carcinoma, an effective amount of an antimetabolite (e.g., a nucleoside analog, e.g., gemcitabine) is administered individually. The step includes delivering an antimetabolite (e.g., nucleoside analog, e.g., A method is provided in which gemcitabine is delivered locally to the bladder. In some embodiments, Urothelial carcinoma of the lower urinary tract is muscle-invasive bladder cancer (MIBC). In some embodiments, Urothelial carcinoma of the lower urinary tract is non-muscle-invasive bladder cancer (NMBIC).

[0054] The term "persistent" or "continuously" as used herein means a period of time. For example, the incubation period for an antimetabolite (e.g., gemcitabine) can range from 24 hours to 3 weeks. This refers to continuous administration.

[0055] The term "individual" as used herein refers to mammals, including humans. This includes, but is not limited to, humans, cattle, horses, cats, dogs, rodents, or primates. i. In some embodiments, the individual is human.

[0056] In this specification, any reference to a value or parameter refers to that value or parameter itself. This includes (and describes) embodiments relating to the above. For example, "about 7 days" includes 7 days.

[0057] These methods can be implemented in an adjuvant situation. An "adjuvant situation" refers to an individual However, the patient has a history of proliferative disorders, particularly cancer, and has undergone surgery (e.g., surgical resection) and radiation therapy. Treatments that include but are not limited to therapy and chemotherapy are generally (but not necessarily) considered. (Iga) refers to a clinical situation that was responsive. However, in the case of a history of proliferative disorders (e.g., cancer) Consequently, these individuals are considered to be at risk of developing the disease. Treatment or administration in the "situation" refers to the subsequent treatment method. The degree of risk (i.e., adjuvant If an individual in a critical situation is considered "high risk" or "low risk," how many That factor, most usually, depends on the severity of the disease at the time of initial treatment. Provided herein The method can also be implemented in a neoadjuvant situation; that is, this method is primary / final It may be performed before treatment. In some embodiments, the individual has been treated previously. In some embodiments, the individuals have not been previously treated. In some embodiments, the treatment is first selected It is an elective treatment.

[0058] The term "effective dose," as used herein, means the amount used to treat a specified disorder, condition, or disease. To improve, alleviate, reduce, and reduce one or more of the symptoms. Refers to an amount of compound or composition sufficient to cause / delay cancer or other unwanted Regarding undesirable cell proliferation, the effective dose reduces tumor size and / or increases tumor growth rate. To reduce the degree of growth (e.g., to suppress tumor growth) or to prevent other undesirable cell proliferation. Contains a sufficient amount to prevent or delay development. In some embodiments, the effective amount is sufficient to prevent development The amount is sufficient to cause a delay. In some embodiments, the effective amount is sufficient to cause the appearance and / or reappearance. A sufficient amount to prevent or delay the onset. The effective dose is 1 or It may be administered in multiple doses, and the effective amount of the drug or composition is (i) to reduce the number of cancer cells. (ii) It may reduce tumor size; (iii) It may prevent cancer cells from invading peripheral organs. It can be inhibited to some extent, slowed down, decelerated, and preferably stopped. (iv) It can inhibit tumor metastasis (i.e., it can slow it down to a certain extent, preferably it (v) may stop; (v) may inhibit tumor growth; (vi) may prevent the appearance of tumors and / or (vii) conditions that can prevent or delay recurrence; and / or (vii) conditions associated with cancer It may be possible to alleviate one or more of the symptoms to some extent.

[0059] In some embodiments, a method for reducing disease progression, comprising an effective amount of an antimetabolite (e.g.) For example, the procedure includes a step of delivering a nucleoside analog (e.g., gemcitabine) to an individual. Antimetabolites (e.g., nucleoside analogs, e.g., gemcitabine) localize to the bladder. A method for local delivery is provided. In some embodiments, a method for reducing tumor volume is provided. And, an effective amount of an antimetabolite (e.g., nucleoside analog, e.g., gemcitabine) The process includes the step of delivering an antimetabolite (e.g., a nucleoside analog) to an individual, and the process includes the step of delivering an antimetabolite (e.g., a nucleoside analog) to an individual. For example, a method is provided in which gemcitabine is delivered locally to the bladder. In terms of form, a method for treating bladder cancer, comprising an effective amount of an antimetabolite (e.g., nucleo The process includes the step of delivering a side analog (e.g., gemcitabine) to an organism, and an antimetabolite (For example, nucleoside analogs, e.g., gemcitabine) are delivered locally to the bladder. A method is provided in which no residual lateral proliferative tumors are present after the procedure.

[0060] In some embodiments, the methods provided herein are intended to improve the quality of life of patients. It is useful. For example, the method provided herein is not applicable to patients who cannot undergo cystectomy. It can be used to provide chronic treatment to patients. In some embodiments, as provided herein The method can be used as palliative care. In some embodiments, the individual with cancer Methods for reducing pain are provided herein.

[0061] In some embodiments, individuals with urothelial carcinoma of the lower urinary tract are sensitized for radiotherapy. A method that involves an effective amount of an antimetabolite (e.g., nucleoside analog, e.g., ge). The process includes the step of delivering mucitabine to an individual, and an antimetabolite (e.g., nucleoside). A method is provided in which a neurotransmitter (e.g., gemcitabine) is delivered locally to the bladder. In one embodiment, this method further includes the step of subjecting the individual to radiotherapy. In this embodiment, radiotherapy is performed after the delivery of an antimetabolite, for example, the delivery of an antimetabolite. It will be performed approximately 1, 2, 3, 4, 5, 10, 15, 20, or 30 days after the date. The radiation intended herein includes, for example, X-rays, gamma rays, and radioisotopes to tumor cells. This includes direct delivery to the body. Other forms of DNA damage factors include, for example, microwaves and UV. Irradiation is also planned. Radiation will be administered in a single dose or in a dose-divided schedule. It can be given in smaller doses than the number of doses. In some embodiments, the dose of radiation is given in radiation therapy. It is lower than conventional doses. For example, the radiation dose is about 95% of the conventional dose, 90 %, 85%, 80%, 75%, 60%, 50%, 40%, 30%, 20%, or 10% It could be any of the following:

[0062] In some embodiments, the antimetabolite is continuously delivered into the bladder. For example, in some In this embodiment, the antimetabolite is allowed to stand for at least about 24 hours (for example, at least about 2, 3 hours). Over a period of 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 days, the bladder It is delivered continuously. In some embodiments, the antimetabolite remains in the bladder for 7 days. They are delivered continuously. The antimetabolites are released at a single rate, or at different rates at different points in time. It can be delivered at a release rate. For example, in some embodiments, the antimetabolite is delivered at a first rate. During this period, it is delivered at a first discharge rate, and thereafter, a second delivery having a second discharge rate. This period continues. In some embodiments, the first release rate is faster than the second release rate (e.g. For example, at least 2×, 3×, 4×, 5× or 10× faster). In some embodiments, Velocity 1 is slower than the second release velocity (for example, at least 2×, 3×, 4×, 5×). (It's 10 times slower).

[0063] In some embodiments, the antimetabolite is approximately 1 mg / day to approximately 300 mg / day, for example, approximately 1mg / day ~ approx. 5mg / day, approx. 5mg / day ~ approx. 10mg / day, approx. 10mg / day ~ approx. 50m g / day, about 50 mg / day to about 100 mg / day, about 100 mg / day to about 225 mg / day (e.g. For example, approximately 140 mg, 160 mg, 180 mg, 200 mg, or 220 mg. It is delivered in a dose of approximately 200 mg / day to approximately 300 mg / day. (Some embodiments) Then, approximately 100 mg to 200 mg of gemcitabine is delivered to the individual. In this scenario, approximately 160 mg of gemcitabine is delivered to the individual over a period of 7 days. In this state, approximately 100 mg to 200 mg of gemcitabine is delivered to the individual over a period of 7 days. In some embodiments, approximately 200 mg to 225 mg of gemcitabine is administered over 21 days. It is delivered to the individual. In some embodiments, approximately 225 mg of the antimetabolite is delivered over 21 days. It is then delivered to the individual. In some embodiments, 225 mg of gemcitabine is delivered over 7 days. It is administered to the individual. In some embodiments, 225 mg of gemcitabine is administered over 21 days. It is administered to the individual.

[0064] In some embodiments, the concentration of the antimetabolite in the urine during the delivery period is approximately 0.1 μg / m³. L~approximately 200 μg / mL, for example, approximately 0~0.5, 0.5~1, 1~2, 2~3, 3~4 , 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-20, 20-30, 30 ~40, 40~60, 60~80, 80~100, 100~150 or 150~200 It is one of the following μg / mL. In some embodiments, the concentration of an antimetabolite in the plasma of an individual is Approximately less than 1 μg / mL, for example, approximately 0.5, 0.4, 0.3, 0.2, 0.1, 0.05. Less than 0.04, 0.03, 0.02, or 0.01 μg / mL. In this embodiment, during the delivery of antimetabolites, antimetabolites in the individual's urine are compared with antimetabolites in the plasma. The ratio of the antisubstance is greater than approximately 500:1. In some embodiments, the plasma concentration of dFdU is The concentration is less than 0.3 μg / mL during delivery of the antimetabolite. In some embodiments, dFd The plasma concentration of U is less than 0.2 μg / mL at the time of delivery of the antimetabolite. In this state, the plasma concentration of dFdU is less than 0.1 μg / mL at the time of delivery of the antimetabolite. In some embodiments, the plasma concentration of dFdU is 0.1 μg / It is between mL and 0.3 μg / mL.

[0065] In some embodiments, the delivery of antimetabolites is carried out in separate phases, with a drug-free period in between. Includes the delivery period of the antimetabolite. Dosage or release rate of the antimetabolite between different delivery periods. These may be the same or different. For example, in some embodiments, the antimetabolites are at least It is delivered over a period of one month, and the delivery period for each antimetabolite is at least one day, and each metabolic The interval between antagonist delivery periods is approximately one week or less. In some embodiments, this method is used. a) The concentration of an antagonist in the urine of the individual is at least about 0.1 μg / mL, the first generation a) duration of antagonist delivery; b) withdrawal period; and c) when the concentration of the antimetabolite in the individual's urine is approximately 0 This includes a delivery period of the second antimetabolite, gemcitabine, higher than 0.1 μg / mL. In some embodiments, the first antimetabolite delivery period is 7 days, and the drug-free period is 14 days. The second antimetabolite delivery period is 7 days. In some embodiments, the antimetabolite The quality is delivered on days 1–7 and 21–28 of the treatment regimen. In some embodiments The antimetabolites are delivered on days 1-14 and 22-34.

[0066] In some embodiments, this method involves two or more that are not separated by a drug-free period. This also includes a long delivery period. In some of these embodiments, the first and second delivery periods are shared. This takes 3 weeks. In some embodiments, the antimetabolite is delivered over a period of 6 weeks. ru.

[0067] In some embodiments, the antimetabolite persists even after delivery has ceased. For example, In one embodiment, the concentration of antimetabolites in urine decreases after the cessation of antimetabolite delivery. Also, over approximately 6, 12, 18, 24, or 36 hours, approximately 0.1 μg / mL The values ​​are also high (for example, approximately 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0. (Higher than either 9 or 1 μg / mL). In some embodiments, the concentration of the antimetabolite The degree is 0.1 to 1 over a period of 6 hours to 7 days, 6 hours to 3 days, or 6 hours to 24 hours. The concentrations are μg / mL, 0.2-0.8 μg / mL, or 0.3-0.7 μg / mL.

[0068] Various methods are used to evaluate the antitumor effect produced by the methods provided herein. It can be used for purposes such as biochemicals like AKT, CD31, Ki67, and TUNEL. The level of markers is used to assess cell death by using immunohistochemistry in tumor material. It can be measured.

[0069] The methods described herein are, for example, for combination therapy in conjunction with the delivery of a second drug. This is particularly appropriate. For example, in some embodiments, urothelial carcinoma of the lower urinary tract in an individual is treated. A method of placing a) an effective amount of an antimetabolite (for example, a nucleoside analog, e.g. a) a) a gemcitabine, and b) a step of delivering an effective amount of a second drug to the individual, Antimetabolites (e.g., nucleoside analogs, e.g., gemcitabine) are localized to the bladder. A method is provided for targeted delivery. In some embodiments, the second agent is an antimetabolite. It is delivered at the time delivery is initiated. In some embodiments, the second agent is an antimetabolite. It is delivered before delivery begins. In some embodiments, the second agent is an antimetabolite delivery. It is delivered after delivery has started. In some embodiments, the second drug is an antimetabolite delivery. It is delivered after the first delivery is completed. The antimetabolite delivery period and the second drug delivery period are relative to each other. It's okay if there are duplicates or not.

[0070] Antimetabolites and second drugs can be delivered via different routes. For example, some In some embodiments, the second drug is delivered systemically. In some embodiments, the second drug is , delivered locally. In some embodiments, the second drug is delivered during the first second drug delivery period. During this period, it is delivered systemically, and then during the second period of the second drug delivery period, it is delivered pharmacokinetically. Local delivery continues. In some embodiments, the second drug is delivered during the first period of the second drug delivery period. It is delivered locally in the first place, and then systemically in the second phase of the second drug delivery period. The following will be discussed. The first period of the second drug delivery period and the second period of the second drug delivery period are as follows: In some embodiments, for example, at least about 1, 2, 3, 4, 5, 6, or 7 days It can be separated by any of the following. In some embodiments, the first period of the second drug delivery period and The second period of the second drug delivery period is, in some embodiments, at least about 1, 2, 3 It can be separated by 4, 5, 6, or 7 weeks.

[0071] In some embodiments, the antimetabolite and the second agent are administered via the same or different route of administration. They will be delivered simultaneously via either method.

[0072] In some embodiments, the antimetabolite and the second drug are delivered by a single delivery device, for example. , delivered via one of the delivery devices described herein. For example, device These are two separate devices, one for antimetabolites and the other for a second drug. The chamber may include, for example, a second drug and an antimetabolite, which may be mixed together. And they are present in the same chamber. In some embodiments, an antimetabolite and a second drug The agents are delivered at the same release rate. In some embodiments, an antimetabolite and a second agent The drug is delivered at different release rates. Different release rates, for example, affect the drug delivery profile. This can be achieved by employing a delivery device of a specific design to achieve the desired result. In one embodiment, an antimetabolite and a second drug are delivered (for example, via the same delivery device) If delivered simultaneously, this method further includes the administration of a second dose of the drug. This can be achieved, for example, by systemic or topical delivery of a second drug.

[0073] The second agent may be any therapeutic agent suitable for the method described herein. In terms of administration methods, the second drug is a chemotherapeutic agent, such as paclitaxel, docetaxel, or carcinoma. A chemotherapeutic agent selected from the group consisting of voplatin, cisplatin, and oxaliplatin. That is the case.

[0074] In some embodiments, a method for treating urothelial carcinoma of the lower urinary tract, comprising an antimetabolite ( For example, the step includes administering gemcitabine (or similar) locally to the bladder in combination with BCG. Methods are provided herein. In some of these embodiments, the method is used for 24 hours ~ The steps involve delivering gemcitabine locally to the individual's bladder over a period of three weeks, and BCG The procedure includes the step of administering a certain substance. In some embodiments, the substance provided herein is a gemworm. It does not include the step of administering BCG to the individual in combination with Tabin.

[0075] In some embodiments, the second agent is an immunomodulatory agent. For example, in some embodiments A method for treating urothelial carcinoma of the lower urinary tract in an individual, comprising: a) an effective amount of an antimetabolite a) a substance (e.g., nucleoside analog, e.g., gemcitabine) and b) an effective amount of immunity The process includes the step of administering a regulatory agent to an individual, and an antimetabolite (e.g., nucleoside an A method is provided in which a log (e.g., gemcitabine) is delivered locally to the bladder. In this embodiment, the immunomodulatory agent is PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, B and T lymphocyte attenuators (BTLA), Killer inhibitor receptors (KIRs), GAL9, TIM3, A2AR, LAG-3, phosphatidyl Dyrserine, CD27, TNF-α, CD33, Siglec-5, Siglec-7, An immunotherapy checkpoint selected from the group consisting of Siglec-9 and Siglec-11 Immune checkpoint inhibitors include, but are not limited to, inhibitors of the immunoprotein. It is a drug. In some embodiments, the immunomodulatory drug is CD40, OX40, ICOS, C D28, CD137 / 4-1BB, CD27, IL-10, TGF-beta, TOR receptor Select from the group consisting of the body and the glucocorticoid-inducible TNFR-related protein GITR. This includes, but is not limited to, agonists of co-stimulatory immune molecules. be.

[0076] In some embodiments, the individual does not receive radiation therapy. In some embodiments, this method This further includes radiotherapy. In some embodiments, the antimetabolite is a neoadjuvant. They are delivered in a specific situation. In some embodiments, the antimetabolite is delivered in an adjuvant situation. In some embodiments, this method further includes a third treatment, which includes surgery, to replace the individual. The delivery of anti-antagonists may be initiated at the time of surgery, before surgery, or after surgery. In this administration method, the delivery of antimetabolites to the individual is initiated during cystoscopy.

[0077] The delivery of antimetabolites (and, in some embodiments, a second agent) described herein. In some embodiments, this can be carried out using an intravesical (intravesical) delivery device. Various intravesical (intravesical) delivery devices are described herein. In some embodiments, Intravesical devices are housings configured for intravesical insertion. ; and a medication form containing an antimetabolite, the housing holds the medication form and the urinary tract It is configured to release an antimetabolite in an amount effective for treating skin cancer. (Some embodiments) Therefore, intravesical (intravesical) drug delivery devices contain antimetabolites and can control their delivery. The retaining shape is configured to release and hold the device in the individual's bladder and urethra. Elastically deformable between the deployment shape and the device's passage through it. Includes woozing. In some embodiments, the device has a first wall (e.g., a cylindrical wall) and The first includes a drug reservoir lumen bordered by a second wall (for example, a disk-shaped wall), The first wall is impermeable to drugs, while the second wall is permeable to antimetabolites. The first wall is impermeable to antimetabolites, and the second wall is permeable to antimetabolites. In some transient other embodiments, the first wall and the second wall are adjacent to each other and together This forms an annular tube that defines the lumen of the drug reservoir. Some of these embodiments The second wall, then, is in the form of a strip extending at least a portion of the length of the structure of the first wall. In some embodiments, the device includes at least two drug reservoir lumens, and some In this embodiment, each reservoir contains a different drug contained therein.

[0078] Antimetabolites are released by osmosis or diffusion, depending on the desired drug release profile. These can be released from the device. In some embodiments, antimetabolites are contained in the housing. The substance is in a non-liquid form, such as tablets, granules, semi-solids, powders, and capsules. The group consists of various non-liquid forms of drug cores, and combinations thereof. Further details will be provided in the document.

[0079] In some embodiments, the antimetabolite is delivered via passive transport. Therefore, passive transport is facilitated transport.

[0080] In some embodiments, urothelial carcinoma of the lower urinary tract is bladder cancer. For example, in some embodiments In terms of form, a method for treating bladder cancer in an individual, a) an effective amount of an antimetabolite ( For example, a nucleoside analog (e.g., gemcitabine), and optionally b) an effective amount The procedure includes the step of administering a second drug (e.g., an immunomodulator) to the individual, and an antimetabolite The substance (e.g., nucleoside analog, e.g., gemcitabine) is delivered locally to the bladder. A method is provided that allows for the treatment of bladder cancer. In some embodiments, bladder cancer is a locally advanced bladder cancer. Or it is metastatic bladder cancer. In some embodiments, the bladder cancer is muscle-invasive bladder cancer. In some embodiments, bladder cancer is non-muscle-invasive bladder cancer. In some embodiments, bladder Bladder cancer is carcinoma in situ. In some embodiments, bladder cancer is treated with BCG (Calmette Gerrit). It is refractory cancer or papillary bladder cancer (caused by Bacillus bacilli).

[0081] The individuals described herein may be mammals, preferably humans. Some embodiments Therefore, the individual is unsuitable for systemic treatment. In some embodiments, the individual has impaired immunity. It has an epidemic lineage. In some embodiments, individuals are resistant to or resistant to chemotherapy. It is inappropriate for legal treatment. In some embodiments, individuals become resistant to other cancer immunotherapies. or is unsuitable for other cancer immunotherapies. In some embodiments, the individual has a low neutrophil count. In some embodiments, individuals are ineligible for cisplatin-based combination therapy. In some embodiments, the individual has not received prior radiation therapy to the bladder. Morphologically, individuals may be reluctant to undergo cystectomy or may be unable to undergo cystectomy. No. In some embodiments, the individual undergoes cystectomy after treatment with an antimetabolite. You may leave it.

[0082] In some embodiments, the level of immune checkpoint proteins is as described herein. It is used as a basis for selecting individuals for treatment using the method described. Morphologically, individuals exhibit high levels of immune checkpoint proteins (e.g., PD-L1). In some embodiments, the individual has low levels of immune checkpoint proteins ( For example, it has PD-L1). In some embodiments, the individual has an immune checkpoint The treatment is selected based on the level of protein (e.g., PD-L1). In the embodiment, the individual has a high level of immune checkpoint protein (e.g., Selected for treatment when it is determined that it has PD-L1. Some embodiments So, if an individual has low levels of immune checkpoint proteins (e.g., PD- If L1) is present, it is selected for treatment.

[0083] In some embodiments, the level of the nucleoside transporter is obtained by using the method described herein. It is used as a basis for selecting individuals for treatment. In some embodiments, The body has a high level of nucleoside transporter (e.g., hENT1). Some embodiments Therefore, the organism has low levels of nucleoside transporters (e.g., hENT1). In the embodiment, the individual is determined based on the level of the nucleoside transporter (e.g., hENT1) , selected for treatment. In some embodiments, individuals are selected if they have a high level of nucleation. If it is determined that an oside transporter (e.g., hENT1) is present, then selected for treatment. In some embodiments, the individual is a low-level nucleoside transporter (e.g., If it has hENT1), it is selected for treatment.

[0084] The effectiveness of the methods described herein can be evaluated by various methods. For example, Regarding the placement method, its effectiveness can be evaluated by tumor growth, tumor reduction, or survival. In some embodiments, the effectiveness of the method is based on the level of one or more markers. The effectiveness of the method is evaluated based on the level of TGF-beta or IL-10. This can be determined accordingly. In some embodiments, the effectiveness of the method is determined by the amount of antimetabolites in the urine and It can be evaluated based on the ratio of its metabolites. For example, the antimetabolite is gemcitabine. In this case, the effectiveness of the method is determined by the ratio of gemcitabine and its metabolites (e.g., dFdU) in the urine. It can be evaluated based on this. For cancer treatments, a ratio below the threshold may indicate effectiveness.

[0085] In some embodiments, pro-inflammatory cytokine production may increase, and anti-inflammatory cytokine production may increase. Production may decrease. The amount of pro-inflammatory cytokines may be localized in the bladder or systemically. It can increase gradually, and similarly, the amount of anti-inflammatory cytokines may increase locally or globally in the bladder. It can be reduced physically. For example, in some embodiments, the level of IL-10 increases. In some embodiments, the level of TGFβ decreases. In some embodiments, interferon The level of gamma (IFN-γ) increases.

[0086] Regulatory T cells, also known as suppressor T cells or T-regs, are T cell immunosuppressors. They are a regulatory population. In cancer, regulatory T cells are recruited to the tumor microenvironment, and effector T cells are formed. It provides an immunosuppressive tumor microenvironment that suppresses cells and reduces the body's immune response to tumors. Regulatory T cells suppress their immunosuppression through the cellular secretion of anti-inflammatory cytokines. Execute the function.

[0087] Therefore, in one embodiment, this method involves an antimetabolite (e.g., nucleoside analgesic). For example, when administering gemcitabine, reducing the number, level, or percentage of regulatory T cells By reducing it, the treatment of urothelial carcinoma of the lower urinary tract is facilitated. Those skilled in the art will know how to adjust the sample Various methods for measuring the presence of nodal T cells, for example, immunologically, regarding relevant markers. Histochemical staining, or flow cytometry or FACS analysis. They will recognize that the level or percentage of regulatory T cells is also CD4+CD2. Compared to conventional T cells, which are 5-, their levels may be relatively reduced.

[0088] Furthermore, or alternatively, the activity of regulatory T cells may decrease upon delivery of antimetabolites. Functional assays, such as cytokine release, are used to measure the activity of regulatory T cells. It can be used for this purpose.

[0089] The number, level, quantity, or activity of regulatory T cells can be measured, for example, in the bladder, tumor microenvironment, or localized area. Local reduction may occur in the lymph nodes. The number, level, quantity, or activity of regulatory T cells may be It can also decrease systemically.

[0090] Cytotoxic T cells target antigens by binding to antigens associated with MHC class I molecules. These are CD8+ T cells that recognize infected or damaged cells. Cytotoxic T cells recognize infected or damaged cells. Furthermore, it induces apoptosis via the caspase cascade, influencing the body's anti-cancer response. It is recognized that it plays an important role in the delivery of antimetabolites. The levels, numbers, and / or activity of these substances may increase, potentially promoting the body's anti-cancer response. For example, The relative levels of cytotoxic T cells may increase compared to inhibitory regulatory T cells, which is because, This can be determined by FACS analysis. Furthermore, or alternatively, the activity of cytotoxic T cells. This can increase, and this can be measured using a functional assay.

[0091] Activated effector CD4+ T cells also produce pro-inflammatory cytokines and proteins. They play a crucial role in inducing an inflammatory response by secreting substances or peptides. It plays a role and is recognized as playing an important part in the body's anti-cancer response. During substance delivery, the levels, number, and / or activity of effector CD4+ T cells increase. This can promote the body's anti-cancer response. For example, the relative rate of effector CD4+ T cells Bell's T cells may increase compared to inhibitory regulatory T cells, which can be determined by FACS analysis. It is possible that, or alternatively, the activity of effector CD4+ T cells may increase, This can be measured using a functional assay.

[0092] In some embodiments, the level of regulatory T cells is controlled by cytotoxic T cells and effectors. The levels of both T cells decrease compared to the levels of regulatory T cells. In some embodiments, the levels of regulatory T cells decrease. This is reduced compared to the level of activated conventional CD4+ / CD25-T cells (Tcon). To reduce. Immune checkpoint inhibitors

[0093] Immunomodulatory agents may be drugs that modulate checkpoint inhibitors. Checkpoint proteins are signaling proteins that play a role in regulating the immune response. It is a signaling protein. Some checkpoint inhibitors respond to extracellular signaling. It is a receptor located on the surface of cells. For example, many checkpoints are ligands. -Initiated by receptor interaction. Once activated, the checkpoint protein Anti-inflammatory responses may include activation of regulatory T cells and inhibition of cytotoxic or killer T cells. Generate the answer. Cancer cells use a method to evade recognition by immune cells, It has been shown that it expresses point proteins. Therefore, checkpoint inhibition The agent can be used to activate the immune system in an individual in order to kill cancer cells. Pardoll, Nature Reviews Cancer, Vol. 12, pp. 252-264 (2012).

[0094] Exemplary checkpoint inhibitors include PD-L1, CTLA4, PD-L2, and PD- 1. B7-H3, B7-H4, HVEM, B and T lymphocyte attenuators (BTLA) ), killer inhibitor receptors (KIRs), GAL9, TIM3, A2AR, LAG-3, phosph Adidylserine, CD27, TNF-α, CD33, Siglec-5, Siglec- 7. This includes inhibitors of Siglec-9 and Siglec-11.

[0095] CTLA-4 signaling inhibits T cell activation, particularly during strong T cell responses. CTLA-4 inhibitors such as anti-CTLA-4 monoclonal antibodies are used. Blockade is more attractive because the suppression of the inhibitory signal leads to the generation of an antitumor T cell response. It has. Both clinical and preclinical data show that CTLA-4 blockade is equivalent to CD4+ It has been shown to produce direct activation of CD8+ effector cells, and is anti-CTLA-4 Monoclonal antibody therapy has shown promise in several cancers, particularly melanoma. Leach et al., Science, Vol. 271: pp. 1734-1736 (1996); Wolchok et al., Oncol Ogist, Vol. 13: Supplement 4: pp. 2-9 (2008).

[0096] Similar to CTLA-4 signaling, PD-1 / PD-L1 modulates the T cell response. Tregs expressing PD-1 have been shown to have an immunosuppressant response. Therefore, PD-1 / PD-L1 expression is thought to play a role in self-tolerance. Regarding cancer, tumor cells use PD-1 and PD to evade recognition by the immune system. - Overexpresses L1. Anticancer therapies that block PD-L1 / PD-1 are effector T It increases cell activity and decreases inhibitory Treg activity, thereby enabling the individual's immune system to recognize tumors. And it enables destruction.

[0097] Various checkpoint inhibitors can be used. For example, checkpoint inhibitors are, It may be an antibody that binds to checkpoint inhibitor proteins and antagonistizes them. Examples of antibodies include anti-PD1 antibodies (nivolumab, pembrilizumab), Pidilizumab), anti-PD-L1 antibody (atezolizumab, BMS-936559, MPD) L-3280A, MEDI7436, AMP224), anti-CTLA4 antibody (ipilimumab) This includes tremelimumab, etc. In some embodiments, checkpoint inhibitors are used. Tagonists can be small molecules or RNAi that target checkpoint inhibitors. In some embodiments, the checkpoint inhibitor is a peptide mime or polypeptide. could be. Immune co-stimulatory molecule agonist

[0098] Immunomodulatory drugs can also be immune costimulatory molecule agonists. Immune costimulatory molecules are immune It is a signaling protein that plays a role in regulating the disease response. These are receptors located on the surface of cells that respond to extracellular signaling. Then, immune costimulatory molecules suppress regulatory T cells and activate cytotoxic or killer T cells. Generate an inflammatory promoting response that may include customization. Therefore, an immune co-stimulatory molecule agonist can be used to activate the immune system in an individual to kill cancer cells. It can be used to activate the immune system in an individual to kill cancer cells.

[0099] Exemplary immune co-stimulatory molecules include CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27 and glucocorticoid-induced TNFR-related protein GITR Any of them is included. For example, OX40 stimulation enhances the survival and activity of effector T cells while suppressing T reg cell function, thereby increasing anti-tumor immunity. It enhances the survival and activity of effector T cells while suppressing T reg cell function, thereby increasing anti-tumor immunity.

[0100] Various immune co-stimulatory molecule agonists can be used. For example, an immune co-stimulatory molecule agonist can be an antibody that binds to and activates an immune co-stimulatory molecule. In some embodiments, the immune co-stimulatory molecule can be an agonist antibody against CD40, OX30 or GITR . In further embodiments, the immune co-stimulatory molecule agonist can be a small molecule that targets and activates an immune co-stimulatory molecule. Dosing regimen

[0101] The following sections describe various aspects (embodiments) of the dosing and treatment areas, all of which are inclusive and applicable to the methods described herein.

[0102] In some embodiments, the invention is a method of treating urothelial carcinoma of the lower urinary tract of an individual, comprising locally delivering an antimetabolite (e.g., a nucleoside analog, e.g., gemcitabine) to the bladder of the individual. Various methods can be used to deliver the antimetabolite. In one embodiment, the drug is by direct injection of a simple solution into the bladder. It can be used. In one embodiment, the drug is by direct injection of a simple solution into the bladder. can be provided. For example, a solution of the drug can be pumped into the bladder continuously or in a pulsatile manner over the treatment period. via a urethral or suprapubic catheter. In another embodiment the drug is released from a device or composition placed in the bladder, and the device or composition releases the drug continuously at a rate effective to produce a desired concentration of the drug in the urine over a specified treatment period. For example, the drug can be released into the urine in the bladder from an intravesical device and then the drug diffuses from the urine into the bladder. At the end of the treatment period, the device can be retrieved from the bladder or removed by resorption, dissolution, excretion or a combination thereof.

[0103] In some embodiments, an antimetabolite (e.g., a nucleoside analog, e.g., gemcitabine) is delivered continuously to the bladder. In some embodiments, the antimetabolite is delivered continuously to the bladder. In some embodiments, the antimetabolite is delivered continuously to the bladder over a period of at least about 6, at least about 12, at least about 18, at least about 24, at least about 36, at least about 48, at least about 60 or at least about 72 hours. In some embodiments, the antimetabolite is delivered to the bladder over a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days or at least about 14 days. In some embodiments, the antimetabolite is delivered to the bladder over a period of from about 1 day to about 14 days, from about 2 days to about 14 days, from about 3 days to about 10 days, from about 4 days to about [[ID=2...]] <...><00...> delivered to the bladder over a period of at least about 1 day to at least about 14 days. In some embodiments, the antimetabolite is delivered to the bladder over a period of from about 1 day to about 14 days, from about 2 days to about 14 days, from about 3 days to about 10 days, from about 4 days to about​​​​​​​​ It is delivered to the bladder over a period of 8 days or approximately 5 to 7 days. In some embodiments, The antimetabolite is delivered to the bladder over a period of approximately 7 days. In some embodiments, Mucitabine is delivered to the bladder over a period of approximately 1 to 30 days. In some embodiments, The antimetabolites are delivered to the bladder over a period of approximately 30 days.

[0104] In some embodiments, gemcitabine is administered to the bladder on days 1-7 and 21-28 of the treatment regimen. A method comprising the step of delivering to the bladder is provided herein.

[0105] In some embodiments, the antimetabolite is continuously delivered into the urine of the bladder.

[0106] In some embodiments, an effective amount of an antimetabolite is delivered locally to the individual's bladder. For example, antimetabolites can be delivered in doses of approximately 1 mg / day to approximately 300 mg / day. In this embodiment, the antimetabolite is administered at approximately 5 mg / day to approximately 250 mg / day, and approximately 10 mg / day to approximately 200 mg / day, approximately 15 mg / day to approximately 100 mg / day, or approximately 15 mg / day to approximately 50 mg It is delivered in a daily dose of approximately 1 mg / day. In some embodiments, the antimetabolite is approximately 5 mg / day. g / day, approx. 10mg / day, approx. 15mg / day, approx. 20mg / day, approx. 23mg / day, approx. 25m g / day, approx. 30mg / day, approx. 35mg / day, approx. 40mg / day, approx. 45mg / day, approx. 50m g / day, about 55 mg / day, about 60 mg / day, about 75 mg / day, about 100 mg / day, about 12 5 mg / day, approximately 150 mg / day, approximately 200 mg / day, approximately 250 mg / day, or approximately 300 mg It is delivered in a dose of g / day.

[0107] The total amount of antimetabolites delivered to an individual during the delivery period is approximately 50 mg to 1000 mg. can range from about 75 mg to about 750 mg, from about 100 mg to about 500 mg, from about 200 mg to about 400 mg or from about 100 mg to about 200 mg. In some embodiments, about 225 mg of the antimetabolite is delivered to the individual. In some embodiments, about 100 - about 225 mg of gemcitabine (e.g., about 140 mg, about 160 mg, about 180 mg, about 200 mg or about 220 mg of the antimetabolite) is delivered to the individual over 7 days. In some embodiments about 100 - about 225 mg of gemcitabine (e.g., about 140 mg, about 160 mg about 180 mg, about 200 mg or about 220 mg of the antimetabolite) is delivered to the individual over 3 weeks In some embodiments, about 100 - about 225 mg of gemcitabine (e.g., about 140 mg, about 160 mg, about 180 mg, about 200 mg or about 220 mg of gem citabine) is administered to the individual over 3 weeks. In some embodiments, 225 mg of gem citabine is administered to the individual over 7 days. In some embodiments, 225 mg of gem citabine is administered to the individual over 3 weeks.

[0108] In some embodiments, the concentration of the antimetabolite in urine is about 0. 1 μg / mL to about 200 μg / mL during the antimetabolite delivery period. In some embodiments, the concentration of the antimetabolite in urine is about 1.0 μg / mL to about 100 μg / mL, about 5.0 μg / mL to about 90 μg / mL, about 10 μg / mL to about 80 μg / mL, about 20 μg / mL to about 70 μg / mL or about 30 μg / mL to about 50 μg / mL. In some embodiments, the concentration of the antimetabolite in urine is about 1.0 μg / mL, about 5 μg / mL, about 10 μg / mL, about 15 μg / m L, approx. 20 μg / mL, approx. 25 μg / mL, approx. 30 μg / mL, approx. 40 μg / mL, approx. 5 0μg / mL, approximately 60μg / mL, approximately 70μg / mL, approximately 80μg / mL, approximately 90μg / This is either mL or approximately 100 μg / mL.

[0109] The concentration of antimetabolites in urine is related to the amount of urine in the bladder throughout the bladder elimination cycle. It can fluctuate depending on the situation. For example, the concentration of antimetabolites in urine after the contents of the bladder have been excreted. This can be approximately 50 μg / mL to approximately 100 μg / mL. On the other hand, immediately before excretion, the urine contains The concentration of antimetabolites is lower, for example, about 0.1 μg / mL to about 10 μg / mL. It is possible. In some embodiments, the average concentration of antimetabolites over the excretion cycle is about 1. 0μg / mL, approximately 5μg / mL, approximately 10μg / mL, approximately 15μg / mL, approximately 20μg / m L, approx. 25μg / mL, approx. 30μg / mL, approx. 40μg / mL, approx. 50μg / mL, approx. 6 0 μg / mL, approximately 70 μg / mL, approximately 80 μg / mL, approximately 90 μg / mL, or approximately 100 μg / mL The concentration is μg / mL. In some variations, the concentration of antimetabolites throughout the excretion cycle is the highest. High concentrations range from approximately 25 μg / mL to approximately 250 μg / mL, and from approximately 50 μg / mL to approximately 200 μg / mL. It is mL or about 100 μg / mL to about 200 μg / mL. In some embodiments, excretion The minimum concentration of antimetabolites throughout the cycle is approximately 0.1 μg / mL to approximately 20 μg / mL. The concentration ranges from approximately 0.1 μg / mL to approximately 10 μg / mL or from approximately 1 μg / mL to approximately 5 μg / mL.

[0110] One advantage of the method provided herein is that a therapeutically effective amount of an antimetabolite is obtained from the antimetabolite. The substance remains in the urine after the delivery of the substance has been completed. For example, in some embodiments, The concentration of antimetabolites in urine remains elevated for at least approximately one day after the termination of antimetabolite delivery. , at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days , at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days , at least about 10 days, at least about 11 days, at least about 12 days, at least about For 13 days or at least about 14 days, the level is higher than about 1 μg / mL. In the administration method, the concentration of antimetabolites in urine was measured between day 1 and day 14, and between day 1 and day 10. During that period, between days 2 and 9, or between days 3 and 8, approximately 1 μg / mL The concentration of antimetabolites in urine is high. In some embodiments, the concentration of antimetabolites in urine is high after the delivery of antimetabolites is complete. After it is tied, at least approximately 1 day, at least approximately 2 days, at least approximately 3 days, at least Approximately 4 days, at least approximately 5 days, at least approximately 6 days, at least approximately 7 days, and at least Approximately 8 days, at least approximately 9 days, at least approximately 10 days, at least approximately 11 days, and at least For at least about 12 days, at least about 13 days, or at least about 14 days, for about 5 Higher than μg / mL. In some embodiments, the concentration of antimetabolites in urine is higher than that of antimetabolites. After the quality delivery is completed, between 1 day and 14 days, between 1 day and 10 days, and between 2 days and 9 days. Over the course of days or between 3 and 8 days, the level is higher than approximately 5 μg / mL. In this embodiment, the concentration of the antimetabolite in the urine decreases after the delivery of the antimetabolite has ended. At least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, less than At least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, less than At least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days , for at least about 13 days or at least about 14 days, from about 10 μg / mL The concentration of antimetabolites in urine is high. In some embodiments, the concentration of antimetabolites in urine is high when the delivery of antimetabolites is terminated. After that, between 1 day and 14 days, between 1 day and 10 days, between 2 days and 9 days, The level was higher than approximately 1 μg / mL between the 3-day and 8-day periods.

[0111] Another advantage of the method provided herein is that significant amounts of antimetabolites are present in the plasma of an individual. To prevent this from happening, antimetabolites are delivered locally to the individual's bladder. In the application method, the concentration of antimetabolites in the plasma of individuals was less than approximately 5 μg / mL and approximately 3 μg / mL. Less than L, less than approximately 1 μg / mL, less than approximately 0.5 μg / mL, less than approximately 0.1 μg / mL, approximately 0 It is less than 0.001 μg / mL or approximately less than 0.0001 μg / mL.

[0112] Since antimetabolites are delivered locally to the bladder, the delivery of antimetabolites involves the individual's urine. The concentration of antimetabolites present in this substance is higher than in plasma, which means that the side effects of antimetabolites are... It may be beneficial to reduce it. For example, local delivery of antimetabolites to the bladder may reduce it systemically. Decreased neutropenia, lymphedema, anemia, and platelet count caused by chemotherapy. It may cause dysphagia, fatigue, pain, hair loss, reproductive dysfunction, or memory impairment. For example, some In this embodiment, the concentration of antimetabolites in the urine of an individual versus the concentration of antimetabolites in the plasma of an individual. The ratio is greater than approximately 100:1, greater than approximately 200:1, greater than approximately 300:1 Larger than approximately 400:1, larger than approximately 500:1, larger than approximately 600:1 i.e., greater than approximately 700:1, or greater than approximately 1000:1.

[0113] It may be advantageous to deliver antimetabolites locally to the bladder more than once. In some embodiments, the antimetabolite is administered at least twice, at least three times, at least It is delivered locally to the individual's bladder four, at least five, or at least ten times. In this embodiment, the antimetabolite is administered for at least 2 weeks, at least 3 weeks, and at least 4 weeks. Over a period of several weeks, at least 5 weeks, at least 6 weeks, or at least 8 weeks, It is delivered several times. In some embodiments, the antimetabolite is delivered for at least one month and For at least two months, at least three months, at least four months, at least five months, and at least Also, over a period of 6 months, at least 12 months, or at least 18 months, multiple times It is delivered. For example, in some embodiments, the antimetabolite is delivered two, three, four, or five times. Or it is delivered locally to the individual's bladder 10 times. In some embodiments, the antimetabolite is, 1 month, 1 month to 18 months, 2 months to 18 months, 3 months to 18 months, 1 month It will be delivered multiple times over a period of one to six months or one to two months. In this administration method, the antimetabolite is delivered locally to the bladder four times. Then, the antimetabolites are delivered locally to the individual's bladder four times, and the interval between each antimetabolite delivery is , for 3 weeks. In some embodiments, the antimetabolite is administered to the individual's bladder over 12 weeks. It is delivered locally.

[0114] In some embodiments, the antimetabolite is delivered multiple times over a period of at least one month, and each The delivery period for the antimetabolite is at least one day. In some embodiments, the antimetabolite is , delivered at least twice over a period of at least one month. In some embodiments, The antimetabolites are delivered at least three times over a period of at least one month. In this embodiment, the antimetabolite is delivered at least three times over a period of at least one month. In some embodiments, the antimetabolite is reduced over a period of at least two months. It is delivered at least four times. In some embodiments, the interval between each delivery period of the antimetabolite is called a drug-free period. The duration is approximately 4 weeks or less, approximately 3 weeks or less, approximately 2 weeks or less, or approximately 1 week or less. In this embodiment, the antimetabolite is delivered over a period of at least one month, and the antimetabolite Each delivery period is at least one day, and the interval between delivery periods (drug-free period) is approximately one week. The following applies: In some embodiments, the interval between each delivery period (drug-free period) is 3 to 50 days. The duration is 3 to 30 days, 5 to 20 days, or 8 to 15 days. In some embodiments, there is a drug-free period. This can last up to four months (for example, one month, two months, three months, or four months).

[0115] In one embodiment, the period of antimetabolite delivery may be separated by a drug-free period, during which metabolism The antagonist is not delivered. For example, in some embodiments, this method delivers the first antagonist Delivery period; drug-free period after the delivery period of the first antimetabolite; and second delivery after the drug-free period. This includes a period. In some embodiments, this method includes a first antimetabolite delivery period of 7 days; A 14-day drug-free period following the delivery of the first antimetabolite; and a 7-day period for the second antimetabolite. This includes a delivery period. In some embodiments, this method involves a first 3-week period without a drug-free period. This includes an antimetabolite delivery period and a subsequent 3-week second antimetabolite delivery period.

[0116] A method for treating muscle-invasive bladder cancer in an individual, comprising administering gemcitabine for 7 days. A method is provided herein that includes the step of locally delivering to the bladder of an individual. In one embodiment, a method for treating muscle-invasive bladder cancer in an individual, comprising gemcitabine A method comprising the step of locally and continuously delivering to an individual's bladder over a period of seven days is described below. Provided in the specification. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual. The law involves the local and continuous delivery of gemcitabine to the individual's bladder over a period of seven days. The procedure involves a step in which gemcitabine is delivered by an intravesical (intravesical) device. A method is provided herein. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual is provided. A method of placing (i) a gemcitabine-releasing intravesical (intravesical) device in the individual's bladder The step involves placing the device in the bladder, and the device remains in the bladder for 7 days, and the gem A method comprising the steps of continuously delivering cytabine to the bladder is provided herein. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, (i) The step involves placing a gemcitabine-releasing intravesical (intravesical) device into the individual's bladder. The device remains in the bladder for 7 days and releases gemcitabine into the bladder cavity (bladder). The intravesical device is described herein as a method comprising the step of passively delivering gemcitabine. It is provided as follows. In some embodiments, it is a method for treating muscle-invasive bladder cancer in an individual. (i) On day 0, the first gemcitabine-releasing intravesical (intravesical) device was used in the individual Steps to place in the bladder, (ii) on day 7, the first gemcitabine-releasing bladder cavity (bladder (iii) Step of removing the device (in the vesicle), on day 21, the second gemcitabine release (iv) Day 28 The method includes the step of removing a second gemcitabine-releasing intravesical (intravesical) device. The method is provided herein. In some of these embodiments, the device is used to deliver into the bladder Before administration, it contains 225 mg of gemcitabine.

[0117] A method for treating muscle-invasive bladder cancer in an individual, comprising approximately 100-500 mg of gem A method comprising the step of locally delivering cytabine to the bladder over a period of seven days is also described herein. Provided. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual. Then, approximately 100 to approximately 225 mg of gemcitabine (for example, approximately 140 mg, approximately 160 mg, approximately 180 mg, approximately 200 mg, or approximately 220 mg) administered locally and continuously to the bladder over 7 days. A method comprising the step of delivering to an individual is provided herein. In some embodiments, the individual A method for treating muscle-invasive bladder cancer, comprising administering gemcitabine over 7 days to an individual The step includes delivering gemcitabine locally and continuously to the bladder, into the bladder cavity (bladder A method for delivery by an internal device is provided herein.

[0118] In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, (i) The step involves placing a gemcitabine-releasing intravesical (intravesical) device into the individual's bladder. The device remained in the bladder for 7 days, and the device contained 225 mg of gemstones. A method comprising steps including a tabin is provided herein. In some embodiments, A method for treating muscle-invasive bladder cancer in the body, wherein (i) on day 0, the first gemshita A step of placing a bottle-discharging intravesical (intravesical) device into the bladder of an individual, The gemcitabine-releasing device of type 1 contains 225 mg of gemcitabine, step, (i i) Step 7: Remove the first gemcitabine-releasing intravesical (intravesical) device. (iii) On day 21, a second gemcitabine-releasing intravesical (intravesical) device was administered individually. A step of placing the body in the bladder, the second gemcitabine-releasing intravesical (intravesical) drug Vice is given 225 mg of gemcitabine in step (iv) and on day 28, step (iv) A method comprising the step of removing two gemcitabine-releasing intravesical (intravesical) devices, Provided herein.

[0119] A method for treating muscle-invasive bladder cancer in an individual, comprising administering gemcitabine for 3 weeks. A method is provided herein that includes the step of locally delivering to the bladder of an individual. In one embodiment, a method for treating muscle-invasive bladder cancer in an individual, comprising gemcitabine A method comprising the step of locally and continuously delivering to an individual's bladder over a period of three weeks is described below. Provided in the specification. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual. The law involves the local and continuous delivery of gemcitabine to the individual's bladder over a period of three weeks. The procedure involves a step in which gemcitabine is delivered by an intravesical (intravesical) device. The law is provided herein.

[0120] In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, (i) The step involves placing a gemcitabine-releasing intravesical (intravesical) device into the individual's bladder. So, gemcitabine-releasing intravesical (intravesical) devices remain in the bladder for 3 weeks. A method comprising the step of continuously delivering gemcitabine to the bladder is described herein. Provided. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual. (i) A gemcitabine-releasing intravesical (intravesical) device is placed inside the bladder of an individual. The gemcitabine-releasing intravesical (intravesical) device is used for 3 weeks. The gemcitabine-releasing intravesical (intravesical) device remains in the bladder and receives gemcitabine. A method including steps for dynamic delivery is provided herein. In some embodiments, A method for treating muscle-invasive bladder cancer in an individual, comprising (i) a first gemcitabine release A step of placing a sexual intravesical (intravesical) device in the bladder of an individual, wherein the first gem Cytabine-releasing intravesical (intravesical) devices remain in the bladder for 3 weeks. (ii) Remove the first gemcitabine-releasing intravesical (intravesical) device. (iii) Place the first gemcitabine-releasing intravesical (intravesical) device in the bladder. Three weeks later, in the step of placing a second gemcitabine-releasing device into the individual's bladder... And the second gemcitabine-releasing intravesical (intravesical) device is used over a period of 3 weeks in the bladder. (iv) Remove any remaining steps and the second gemcitabine-releasing device in the bladder. A method comprising the step of is provided herein.

[0121] A method for treating muscle-invasive bladder cancer in an individual, wherein more than 225 mg of gemworms A method including the step of locally delivering Tabin to the bladder over a period of three weeks is also provided herein. Provided. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, The treatment involves delivering gemcitabine at a dose greater than 225 mg to the bladder locally and continuously over a period of three weeks. Methods including the steps are provided herein. In some of these embodiments, gemshita Approximately 80% of the vials are delivered to the bladder in the first week, and about 20% of gemcitabine is delivered in the second and It is delivered to the bladder in the third week. In some embodiments, it is used to treat muscle-invasive bladder cancer in individuals. This method involves administering more than 225 mg of gemcitabine to the individual's bladder for three weeks. The step includes delivering gemcitabine locally and continuously to the intravesical cavity (intravesical) A method for delivery by vice is provided herein.

[0122] A method for treating muscle-invasive bladder cancer in an individual, comprising approximately 225 mg of gemcitabine. A method comprising the step of locally delivering to the bladder over a period of three weeks is also provided herein. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, comprising about 2 The procedure includes a step of delivering 25 mg of gemcitabine locally and continuously to the bladder over a period of three weeks. Methods are provided herein. In some of these embodiments, about 80% gemcitabine % is delivered to the bladder in the first week, and about 20% of gemcitabine is delivered to the bladder in the second and third weeks. It is delivered to the bladder. In some embodiments, it is used in a method for treating muscle-invasive bladder cancer in an individual. In addition, approximately 225 mg of gemcitabine is administered locally and continuously to the individual's bladder over a period of 3 weeks. The step includes delivering gemcitabine by an intravesical (intravesical) device. A method for doing so is provided herein.

[0123] In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, (i) The step involves placing a gemcitabine-releasing intravesical (intravesical) device into the individual's bladder. The device remained in the bladder for three weeks, and the device contained 225 mg of gemstones. A method comprising steps including a tabin is provided herein. In some embodiments, A method for treating muscle-invasive bladder cancer in the body, comprising: (i) gemcitabine-releasing bladder cavity The step of placing an intra-bladder device in the bladder of an individual, wherein the device lasts for 3 weeks. It remains in the bladder for approximately 22 hours, and gemcitabine-releasing intravesical (intravesical) devices are used for about 22 hours. A method comprising the step of passively delivering 5 mg of gemcitabine is provided herein. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, (i ) The first gemcitabine-releasing intravesical (intravesical) device is placed in the bladder of the individual. The first gemcitabine-releasing intravesical (intravesical) device lasts for 3 weeks. It remains in the bladder, and the first gemcitabine-releasing intravesical (intravesical) device is 225 (ii) A first gemcitabine-releasing intravesical (bladder) containing mg of gemcitabine. (iii) Steps to remove the device (intravesical), (iii) first gemcitabine-releasing intravesical (bladder) Three weeks after the intravesical device was placed in the bladder, a second gemcitabine-releasing device was placed in the individual The step of placing in the bladder, the second gemcitabine-releasing intravesical (intravesical) drug Vice remained in the bladder for three weeks, and a second gemcitabine-releasing intravesical cavity (bladder) (Internal) The device contains 225 mg of gemcitabine, step (iv) second A method comprising the step of removing a mucitabine-releasing device is provided herein.

[0124] In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, (i) The step involves placing a gemcitabine-releasing intravesical (intravesical) device into the individual's bladder. The device remains in the bladder for three weeks, consuming a total of more than 225 mg of gem. A method comprising the steps of continuously delivering cytabine to the bladder is provided herein. In some embodiments, a method for treating muscle-invasive bladder cancer in an individual, (i) The step involves placing a gemcitabine-releasing intravesical (intravesical) device into the individual's bladder. The device remains in the bladder for 3 weeks and releases gemcitabine into the bladder cavity (bladder). The intravesical device passively delivers more than 225 mg of gemcitabine, step Methods including the above are provided herein. In some embodiments, a muscle-infiltrating bladder in an individual is A method for treating the condition, comprising: (i) a first gemcitabine-releasing intravesical (intravesical) device The step of placing the first gemcitabine-releasing bladder cavity (bladder) in the individual's bladder. The (intravesical) device remains in the bladder for three weeks and enters the first gemcitabine-releasing bladder cavity. The intra-bladder device delivers more than 225 mg of gemcitabine to the bladder. (ii) the step of removing the first gemcitabine-releasing intravesical (intravesical) device. (iii) A first gemcitabine-releasing intravesical (intravesical) device is placed in the bladder. A week later, the procedure involved placing a second gemcitabine-releasing device into the individual's bladder. The second gemcitabine-releasing intravesical (intravesical) device was administered to the bladder for three weeks. The second gemcitabine-releasing intravesical (intravesical) device remains in place, and the 225 mg version is better than the 225 mg version. (iv) A second gemcitabine release, delivered to the bladder. A method comprising the step of removing a sex device is provided herein.

[0125] A method for treating non-muscle-invasive bladder cancer in an individual, comprising administering gemcitabine for 7 days A method comprising the step of locally delivering to the bladder of an individual is provided herein. In one embodiment, a method for treating non-muscle-invasive bladder cancer in an individual, wherein gemshita A method comprising the step of locally and continuously delivering a vial to the bladder of an individual over a period of seven days. , provided herein. In some embodiments, non-muscle-invasive bladder cancer in an individual is treated. This method involves locally and continuously delivering gemcitabine to the individual's bladder over a period of 7 days. The steps include reaching a specific point, and gemcitabine is delivered by an intravesical (intravesical) device. Methods are provided herein. In some embodiments, non-muscle-infiltrating bladder in an individual A method for treating cancer, comprising (i) a gemcitabine-releasing intravesical (intravesical) device The step involves placing the device in the individual's bladder, and the device remains in the bladder for 7 days. A method comprising the step of continuously delivering gemcitabine to the bladder is provided herein. It is provided. In some embodiments, it is a method for treating non-muscle-invasive bladder cancer in an individual. (i) On day 0, the first gemcitabine-releasing intravesical (intravesical) device was placed in the individual's bladder. Steps to place in the bladder, (ii) On day 7, the first gemcitabine-releasing intravesical (bladder) (iii) step of removing the device, on day 21, second gemcitabine-releasing bladder (iv) on day 28, a method comprising the step of removing a second gemcitabine-releasing intravesical (intravesical) device. However, this is provided herein.

[0126] A method for treating non-muscle-invasive bladder cancer in an individual, comprising approximately 225 mg of gemcitabine. A method comprising the step of locally delivering the drug to the bladder over a period of seven days is also provided herein. In some embodiments, a method for treating non-muscle-invasive bladder cancer in an individual, Approximately 100-225 mg of gemcitabine (for example, approximately 140 mg, approximately 160 mg, approximately 18 mg) (0 mg, approximately 200 mg, or approximately 220 mg of gemcitabine) administered locally to the bladder over 7 days. A method comprising the step of delivering continuously is provided herein. In some embodiments This is a method for treating non-muscle-invasive bladder cancer in an individual, using approximately 100 to 225 mg gemcitabine (for example, approximately 140 mg, approximately 160 mg, approximately 180 mg, approximately 200 mg) (Approximately 220 mg of gemcitabine) is administered locally and continuously to the individual's bladder over 7 days. The delivery step includes delivering gemcitabine by an intravesical (intravesical) device. A method for doing so is provided herein.

[0127] In some embodiments, a method for treating non-muscle-invasive bladder cancer in an individual, (i )In the step of placing a gemcitabine-releasing intravesical (intravesical) device into the bladder of an individual The device remained in the bladder for 7 days, and the device contained 225 mg of gem. A method comprising steps including cytabine is provided herein. In some embodiments, A method for treating non-muscle-invasive bladder cancer in an individual, wherein (i) on day 0, the first gem The step of placing a cytabine-releasing intravesical (intravesical) device into the bladder of an individual, The first gemcitabine-releasing intravesical (intravesical) device delivers 225 mg of gemcitabine. Step (ii) on day 7, the first gemcitabine-releasing intravesical (intravesical) drug Steps to remove Vice, (iii) on day 21, second gemcitabine-releasing intrabladder cavity A step of placing the (intravesical) device in the individual's bladder, and a second gemcitabine release The sexual device contains 225 mg of gemcitabine, step (iv) on day 28. a method comprising the step of removing a second gemcitabine-releasing intravesical (intravesical) device. However, this is provided herein.

[0128] In some embodiments, this method is used when the concentration of antimetabolites in the urine of an individual is approximately 0.1 μg / A first antimetabolite delivery period higher than mL; a drug-free period after the first antimetabolite delivery period. During the drug-free period; and when the concentration of antimetabolites in the individual's urine is higher than approximately 0.1 μg / mL. This includes a subsequent second antimetabolite delivery period. In some embodiments, this method is performed in the urine of an individual. The first antimetabolite delivery period, in which the concentration of the antimetabolite is higher than approximately 5 μg / mL; The drug-free period after the delivery period of the antimetabolite; and the concentration of the antimetabolite in the individual's urine is approximately 5 μg. Includes a second antimetabolite delivery period after the drug-free period, with a concentration higher than g / mL. (Some embodiments) Therefore, this method is used when the concentration of antimetabolites in the individual's urine is higher than approximately 7 μg / mL. The duration of antimetabolite delivery; the drug-free period after the first antimetabolite delivery period; and the urine of the individual If the concentration of the antimetabolite is higher than approximately 7 μg / mL, the second antimetabolite transport after the drug-free period. This includes the delivery period. In some embodiments, this method is used when the concentration of antimetabolites in the individual's urine is approximately First antimetabolite delivery period higher than 10 μg / mL; first antimetabolite delivery period Subsequent drug-free period; and the concentration of antimetabolite in the individual's urine is higher than approximately 10 μg / mL. This includes a second antimetabolite delivery period after the drug-free period. In some embodiments, this method is individual The first antimetabolite delivery is characterized by a concentration of antimetabolites in the body's urine higher than approximately 15 μg / mL. Duration; drug-free period after the first antimetabolite delivery period; and concentration of antimetabolites in the individual's urine. This includes a second antimetabolite delivery period after the drug-free period, where the concentration is higher than approximately 15 μg / mL.

[0129] In some embodiments, this method is used when the concentration of antimetabolites in the urine of an individual is 0.1 to 15 μg. The first antimetabolite delivery period is at a concentration of g / mL; the drug-free period follows the first antimetabolite delivery period. During the drug-free period; and when the concentration of antimetabolites in the urine of the individual is 0.1-15 μg / mL. This includes a subsequent second antimetabolite delivery period. In some embodiments, this method is performed in the urine of an individual. The concentration of the antimetabolite is 1-15 μg / mL; the first antimetabolite delivery period; The drug-free period after the delivery period of the antimetabolite; and the concentration of the antimetabolite in the individual's urine is 1-1 This includes a second antimetabolite delivery period after a drug-free period, at a concentration of 5 μg / mL. (Some embodiments) Therefore, this method is used when the concentration of antimetabolites in the urine of an individual is 3-10 μg / mL. The duration of antimetabolite delivery; the drug-free period after the first antimetabolite delivery period; and the urine of the individual The concentration of the antimetabolite is 3-10 μg / mL, and the second antimetabolite is delivered after the drug-free period. Includes delivery period.

[0130] The concentration of antimetabolites in an individual's urine may increase for at least a portion of the drug-free period. For example, the concentration of antimetabolites in urine was approximately 1 μg over at least part of the drug-free period. It may be higher than g / mL. In some embodiments, the concentration of antimetabolites in the urine of an individual is , higher than approximately 5 μg / mL for at least a portion of the drug-free period. (Some embodiments) So, the concentration of antimetabolites in the individual's urine was approximately over at least part of the drug-free period. It is higher than 7 μg / mL. In some embodiments, the concentration of antimetabolites in the urine of an individual is higher than 7 μg / mL. For at least part of the duration of treatment, the concentration is higher than approximately 10 μg / mL. In some embodiments, The concentration of the antimetabolite should be 1 μg / mL to 1 μg / mL for at least a portion of the drug-free period. The concentration is 0 μg / mL.

[0131] In some embodiments, the concentration of antimetabolite in the individual's urine is at least 1 / of the drug-free period. Over four periods, the levels are higher than approximately 1 μg / mL. In some embodiments, metabolic antagonists in the urine of individuals The concentration of the substance remains higher than approximately 5 μg / mL for at least one-quarter of the drug-free period. In one embodiment, the concentration of the antimetabolite in the individual's urine is at least 1 / 4 of the drug-free period. The levels are consistently higher than approximately 7 μg / mL. In some embodiments, the levels of antimetabolites in the urine of individuals are higher than those of antimetabolites in urine. The concentration remains higher than approximately 10 μg / mL for at least one-quarter of the drug-free period. In this embodiment, the concentration of the antimetabolite in the individual's urine is maintained for at least 1 / 4 of the drug-free period. However, the concentration is between 1 μg / mL and 10 μg / mL.

[0132] In some embodiments, the concentration of antimetabolite in the individual's urine is at least 2 minutes after the drug-free period. Over a certain range, it is higher than approximately 1 μg / mL. In some embodiments, metabolic anthracites in the urine of individuals. The concentration of the antisubstance remained higher than approximately 5 μg / mL for at least half of the drug-free period. In some embodiments, the concentration of antimetabolites in the individual's urine is at least 2 minutes after the drug-free period. Over a certain range, it is higher than approximately 7 μg / mL. In some embodiments, metabolic angiogenesis in the urine of individuals. The concentration of the antisubstance remained higher than approximately 10 μg / mL for at least half of the drug-free period. i. In some embodiments, the concentration of antimetabolite in the individual's urine is at least 2 during the drug-free period. The concentration ranges from 1 μg / mL to 10 μg / mL over a 1 / 2 range.

[0133] In some embodiments, the concentration of antimetabolites in the individual's urine is at least 3 / of the drug-free period. Over four periods, the levels are higher than approximately 1 μg / mL. In some embodiments, metabolic antagonists in the urine of individuals The concentration of the substance remains higher than approximately 5 μg / mL for at least three-quarters of the drug-free period. In one embodiment, the concentration of the antimetabolite in the individual's urine is at least 3 / 4 of the drug-free period. The levels are consistently higher than approximately 7 μg / mL. In some embodiments, the levels of antimetabolites in the urine of individuals are higher than those of antimetabolites in urine. The concentration remains higher than approximately 10 μg / mL for at least three-quarters of the drug-free period. In this embodiment, the concentration of the antimetabolite in the individual's urine is maintained for at least 3 / 4 of the drug-free period. However, the concentration is between 1 μg / mL and 10 μg / mL.

[0134] In some embodiments, the concentration of antimetabolites in the individual's urine remains high throughout the drug-free period. It can increase. For example, the concentration of antimetabolite can increase to about 1 μg / mL throughout the entire drug-free period. The concentration may also be high. In some embodiments, the concentration of antimetabolites in the urine of an individual during the drug-free period. Overall, the levels are higher than approximately 5 μg / mL. In some embodiments, metabolic anthracite levels are found in the urine of individuals. The concentration of the antisubstance remains higher than approximately 7 μg / mL throughout the entire drug-free period. (Some embodiments) Therefore, the concentration of antimetabolites in the individual's urine remained at approximately 10 μg / mL throughout the entire drug-free period. It is higher than that. In some embodiments, the concentration of antimetabolites in the individual's urine is higher throughout the drug-free period. The concentration ranges from 1 μg / mL to 10 μg / mL.

[0135] In some embodiments, this method is performed at least once every three months for about one year. The method includes the step of delivering an antimetabolite to an individual. In some embodiments, the method is about 2 Over the course of a year, the step of delivering an antimetabolite to the individual at least once every three months. Includes. In some embodiments, this method involves at least one 3-month interval over a period of about 3 years. The method includes the step of delivering an antimetabolite to an individual. In some embodiments, this method is A step in which an antimetabolite is delivered to the individual at least once every six months over a period of approximately one year. Includes p. In some embodiments, this method is performed at least every 6 months for about 2 years. The process also includes the step of delivering an antimetabolite to the individual. In some embodiments, this method This involves delivering antimetabolites to the individual at least once every six months for approximately three years. Includes steps.

[0136] The rate of release of antimetabolites can vary throughout the delivery process. For example, some actual In this application method, the antimetabolite is released at a first rate during the first stage of delivery. Step 1: An antimetabolite is delivered, followed by a second phase of delivery with a second release rate. This includes the first release rate, which is faster than the second release rate. In other embodiments, the first release rate is slower than the second release rate. This method delivers an antimetabolite at a first dose at the first stage of delivery, and The process then includes the step of delivering a second dose at a second time of delivery. In some embodiments, In some embodiments, the first and second periods are continuous. The timing is separated by the drug-free period.

[0137] The second drug may be delivered locally and / or systemically at different delivery times. For example, in some embodiments, the second drug is delivered at a first time during the second drug delivery period. It is delivered systemically, followed by local delivery during the second phase of the second drug delivery period. In some embodiments, the second drug is delivered locally at the first time of the second drug delivery period. It is delivered locally, followed by systemic delivery during the second phase of the second drug delivery period. In some of these embodiments, the first timing of the second drug delivery period and the second drug delivery period The second period of the second delivery period will be separated by at least approximately one month.

[0138] The antimetabolite and the second drug may be delivered simultaneously or sequentially. In this configuration, the antimetabolite and the second drug are delivered via a single delivery device.

[0139] The antimetabolite and the second drug are delivered at the same release rate to provide a synergistic effect. It may be advantageous to do so. In other embodiments, the antimetabolite and the second agent are different It can be delivered at a release rate slower than the delivery rate of the second drug. For example, an antimetabolite can be delivered at a slower rate than the delivery rate of the second drug. It can be delivered at a faster rate, or the antimetabolite can be delivered at a faster rate than the rate of delivery of the second drug. It can be delivered.

[0140] In some embodiments, this method is used for the delivery of antimetabolites and immunomodulatory agents, etc. This involves the delivery of two drugs. Various doses of immunomodulatory drugs are used, depending on the specific immunomodulatory drug being used. It may be used in an agent-dependent manner. The amount of immunomodulatory drug delivered to the individual is as monotherapy. When obtained based on the approved dosage of immunomodulatory agents, or when used as monotherapy. The dose may be higher or lower than the dose of the immunomodulatory drug being delivered. For example, the immunomodulatory drug is approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 15 or approximately It can be delivered in a dose of 20 mg / kg.

[0141] In some embodiments, the immunomodulatory agent may include the anti-PD1 antibody nivolumab, approximately 3 mg. It can be delivered in doses of / kg. In some embodiments, nivolumab is administered at a dose of 3 mg / kg every two weeks. It can be delivered in a dose of kg. In some embodiments, nivolumab is combined with ipilimumab. They can be delivered together. In some of these embodiments, nivolumab is delivered in a dose of 1 mg / kg. It may be delivered by [method], followed by ipilimumab in four doses every three weeks on the same day, then [method]. This may be followed by nivolumab at a dose of 3 mg / kg every two weeks. In some embodiments, immunotherapy is performed. The therapeutic agent may contain the anti-PD1 antibody pembrolizumab, administered at a dose of 2 mg / kg every 3 weeks. It may be administered.

[0142] In some embodiments, the second agent may be delivered before the initiation of antimetabolite delivery. In some embodiments, the second agent may be delivered after the termination of antimetabolite delivery. In some embodiments, the second agent may be administered during the antimetabolite delivery period. In some embodiments, the delivery period of the antimetabolite and the delivery period of the second drug overlap. Therefore, the delivery period of the antimetabolite and the delivery period of the second drug do not overlap.

[0143] In some embodiments, the second drug may be delivered during the drug-free period. The second drug is administered during the delivery period of the first antimetabolite or the delivery period of the second antimetabolite. It can be delivered to.

[0144] In some embodiments, the methods provided herein involve a period of at least about 24 hours. The steps include delivering an effective amount of an antimetabolite to the individual and delivering an effective amount of a second drug. The method includes the step of doing so. In some embodiments, the method provided herein includes at least about Steps for delivering an effective amount of an antimetabolite to an individual over a period of 48 hours and effective amount The method includes the step of delivering a second drug. In some embodiments, the method provided herein The law requires that an effective amount of antimetabolite be delivered to the individual over a period of at least approximately 60 hours. The procedure includes the step of administering a step and an effective amount of a second drug. In some embodiments, the present invention The method provided in the details involves providing an effective amount of an antimetabolite over a period of at least approximately 72 hours. The procedure includes the steps of delivering a certain substance to an individual and delivering an effective amount of a second drug. In embodiments, the method provided herein is effective for a period of at least about 7 days. The steps involve delivering a certain amount of antimetabolite to the individual and delivering an effective amount of a second drug. Includes pu.

[0145] In some embodiments, the method provided herein involves a period between 24 hours and about one month. The steps of delivering an effective amount of an antimetabolite to the individual over time and an effective amount of a second drug The method includes the step of delivering to an individual. In some embodiments, the method provided herein is The system delivers an effective amount of antimetabolite to the individual over a period of time between approximately 24 hours and approximately 21 days. The process includes a step of delivering an effective amount of a second drug to an individual. In some embodiments, The method provided herein is effective over a period of time between approximately 24 hours and approximately 14 days. The steps involve delivering a certain amount of an antimetabolite to the individual and delivering an effective amount of a second drug to the individual. The steps include. In some embodiments, the methods provided herein involve about 24 hours to about 7 The steps of delivering an effective amount of an antimetabolite to an individual over a period of several days and the effective amount The process includes the step of delivering a second drug to an individual.

[0146] In some embodiments, the method provided herein involves metabolizing an effective amount over approximately 7 days. The steps of delivering an antagonist to the individual and delivering an effective amount of a second drug to the individual. Includes. In some embodiments, the method provided herein provides an effective amount over about three weeks. The steps of delivering an antimetabolite to the individual and delivering an effective amount of a second drug to the individual. Includes steps. In some embodiments, the methods provided herein extend over approximately 6 weeks. The steps involve delivering an effective amount of an antimetabolite to the individual and delivering an effective amount of a second drug to the individual. This includes the step of doing so.

[0147] In some embodiments, the method provided herein involves a period between 24 hours and about one month. The steps of delivering an effective amount of an antimetabolite to the individual over time and an effective amount of a second drug The step includes delivering the second drug to the individual, and when the second drug is delivered, the metabolic anther in the individual's urine The concentration of the antisubstance is less than approximately 1 μg / mL. In some embodiments, as provided herein The method involves administering an effective amount of an antimetabolite to an individual over a period of approximately 24 hours and approximately 21 days. The steps include delivering to and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is less than approximately 1 μg / mL. In some embodiments, the method provided herein is used between approximately 24 hours and approximately 14 days. The steps of delivering an effective amount of an antimetabolite to an individual over a period of time and a second effective amount The process includes the step of administering the drug to an individual, and when the immunomodulatory drug is delivered, the individual's urine The concentration of the antimetabolite is less than approximately 1 μg / mL. In some embodiments, as specified herein The method provided involves administering an effective amount of an antimetabolite over a period of approximately 24 hours to 7 days. The process includes the steps of delivering to an individual and delivering an effective amount of a second drug to the individual. When drug 2 is delivered, the concentration of the antimetabolite in the individual's urine is less than approximately 1 μg / mL. That is the case.

[0148] In some embodiments, the method provided herein involves a period between 24 hours and about one month. The steps of delivering an effective amount of an antimetabolite to the individual over time and an effective amount of a second drug The process includes administering the second drug to an individual, and when the second drug is delivered, the metabolic anther in the individual's urine The concentration of the antisubstance is less than approximately 5 μg / mL. In some embodiments, as provided herein The method involves administering an effective amount of an antimetabolite to an individual over a period of approximately 24 hours and approximately 21 days. The steps include delivering to and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is less than approximately 5 μg / mL. In some embodiments, the method provided herein is used between approximately 24 hours and approximately 14 days. The steps of delivering an effective amount of an antimetabolite to an individual over a period of time and a second effective amount The process includes the step of administering a drug to an individual, and when the second drug is delivered, the individual's urine contains a substitute The concentration of the anti-antagonist is less than approximately 5 μg / mL. In some embodiments, provided herein The method involves administering an effective amount of an antimetabolite to an individual over a period of approximately 24 hours to 7 days. The steps include delivering to and administering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is less than approximately 5 μg / mL. ru.

[0149] In some embodiments, the method provided herein involves a period between 24 hours and about one month. The steps of delivering an effective amount of an antimetabolite to the individual over time and an effective amount of a second drug The step includes delivering the second drug to the individual, and when the second drug is delivered, the metabolic anther in the individual's urine The concentration of the antisubstance is less than approximately 15 μg / mL. In some embodiments, as provided herein The method involves administering an effective amount of an antimetabolite over a period of approximately 24 hours to approximately 21 days. The process includes the steps of delivering to the body and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is less than approximately 15 μg / mL. In some embodiments, the method provided herein involves approximately 24 hours and approximately 14 days. The steps of delivering an effective amount of an antimetabolite to an individual over a period of time and an effective amount The process includes the step of delivering two drugs to an individual, wherein when the second drug is delivered, the individual's urine The concentration of the antimetabolite is less than approximately 15 μg / mL. In some embodiments, as specified herein. The method provided involves delivering an effective amount of antimetabolite over a period of approximately 24 hours to 7 days. The steps include delivering a second drug to an individual and delivering an effective amount of a second drug to the individual. When the second drug is delivered, the concentration of the antimetabolite in the individual's urine is approximately 15 μg / mL. It is less than.

[0150] In some embodiments, the method provided herein involves a period between 24 hours and about one month. The steps of delivering an effective amount of an antimetabolite to the individual over time and an effective amount of a second drug The step includes delivering the second drug to the individual, and when the second drug is delivered, the metabolic anther in the individual's urine The concentration of the antisubstance is higher than approximately 1 μg / mL. In some embodiments, as provided herein The method involves administering an effective amount of an antimetabolite to an individual over a period of approximately 24 hours and approximately 21 days. The steps include delivering to and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is higher than approximately 1 μg / mL. i. In some embodiments, the method provided herein is used between approximately 24 hours and approximately 14 days. The steps of delivering an effective amount of an antimetabolite to an individual over a period of time and a second effective amount The process includes the step of delivering a drug to an individual, wherein when the second drug is delivered, the individual's urine contains a substitute The concentration of the anti-antagonist is higher than approximately 1 μg / mL. In some embodiments, provided herein The method involves administering an effective amount of an antimetabolite to an individual over a period of approximately 24 hours to 7 days. The steps include delivering to and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is higher than approximately 1 μg / mL. stomach.

[0151] In some embodiments, the method provided herein involves a period between 24 hours and about one month. The steps of delivering an effective amount of an antimetabolite to the individual over time and an effective amount of a second drug The step includes delivering the second drug to the individual, and when the second drug is delivered, the metabolic anther in the individual's urine The concentration of the antisubstance is higher than approximately 5 μg / mL. In some embodiments, as provided herein The method involves administering an effective amount of an antimetabolite to an individual over a period of approximately 24 hours and approximately 21 days. The steps include delivering to and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is higher than approximately 5 μg / mL. i. In some embodiments, the method provided herein is used between approximately 24 hours and approximately 14 days. The steps of delivering an effective amount of an antimetabolite to an individual over a period of time and a second effective amount The process includes the step of delivering a drug to an individual, wherein when the second drug is delivered, the individual's urine contains a substitute The concentration of the anti-antagonist is higher than approximately 5 μg / mL. In some embodiments, provided herein The method involves administering an effective amount of an antimetabolite to an individual over a period of approximately 24 hours to 7 days. The steps include delivering to and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is higher than approximately 5 μg / mL. stomach.

[0152] In some embodiments, the method provided herein involves a period between 24 hours and about one month. The steps of delivering an effective amount of an antimetabolite to the individual over time and an effective amount of a second drug The step includes delivering the second drug to the individual, and when the second drug is delivered, the metabolic anther in the individual's urine The concentration of the antisubstance is higher than approximately 15 μg / mL. In some embodiments, as provided herein The method involves administering an effective amount of an antimetabolite over a period of approximately 24 hours to approximately 21 days. The process includes the steps of delivering to the body and delivering an effective amount of a second drug to the individual, When the drug is delivered, the concentration of the antimetabolite in the individual's urine is approximately 15 μg / mL or higher. The cost is also high. In some embodiments, the method provided herein involves about 24 hours and about 14 days. The steps of delivering an effective amount of an antimetabolite to an individual over a period of time and an effective amount The process includes the step of delivering two drugs to an individual, wherein when the second drug is delivered, the individual's urine The concentration of the antimetabolite is higher than approximately 15 μg / mL. In some embodiments, as specified herein. The method provided involves delivering an effective amount of antimetabolite over a period of approximately 24 hours to 7 days. The steps include delivering a second drug to an individual and delivering an effective amount of a second drug to the individual. When the second drug is delivered, the concentration of the antimetabolite in the individual's urine is approximately 15 μg / mL. It's higher than that.

[0153] The second drug can be delivered locally or systemically to the individual's bladder. For example, the second The drug is administered via an intravesical device, bladder pump, catheter, or injection to the bladder. The second drug can be delivered intravesically. The second drug can also be delivered orally, parenterally, or intravenously.

[0154] In some embodiments, the second agent is delivered systemically, followed by local delivery of an antimetabolite. Delivery continues. In some embodiments, the second drug is first delivered systemically, and then locally. It is delivered to the target. In some embodiments, the second drug is first administered topically, and then It is administered systemically.

[0155] Antimetabolites include cytidine analogs, uracil analogs, purine analogs, and deoxygenated compounds. Adenosine analogs, deoxycytosine analogs, guanosine analogs, deoxyguanosine Deoxyguanasine analogs, thymidine analogs, and deoxyuridine (deoxyura This includes analogs. An example of a nucleoside analog is azacitidine (azalit). adine, decitabine, cytanabine, gemcitabine, 5-fluorouracil Lu, capcitabine, azathioprine, mercaptopurine, thioguanine , fludarabine, vidarabine, cytarabine, lamivudine, zalcitabine, abacavir, Cyclovir, Entecavir, Stabuzine, Terbivudine, Zidovudine, Idoxuridine It also contains trifluridine.

[0156] In another embodiment, the methods provided herein involve antimetabolites, immunomodulatory agents and This may include the delivery of various therapeutic agents. In some embodiments, further agents may include Calmet G. Bacillus gallis-galli (BCG). Further therapeutic agents are also described herein. These could be inhibitors, antagonists, or immunocostimulatory molecules. For example, further therapeutic agents These could be anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.

[0157] A second or further agent may be an additional chemotherapeutic agent, such as oxaliplatin, cis. Platin, docetaxel, carboplatin, docetaxel, paclitaxel, anti-VEGF Antibodies, antimetabolites (including nucleoside analogs), platinum-based drugs, alkylating agents , tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkaloids (vinca alkloids, transition metal complexes, proteasome inhibitors, macrolides and topoisomers -ase inhibitors may also be included. In some embodiments, the chemotherapeutic agent is a platinum-based drug, e.g. For example, carboplatin, rapamycin or its derivatives, and geldanamycin or Its derivatives (e.g., 17-allylaminogeldanamycin (17-AAG)), retino Idoids, drugs that disrupt microtubule formation (e.g., colchicine and its derivatives), anti-angiogenic agents These include drugs, therapeutic antibodies, and EGFR-targeting agents.

[0158] In some embodiments, the methods provided herein are used in conjunction with radiation therapy or surgery. The procedure includes the step of locally administering an antimetabolite (e.g., gemcitabine) to the bladder. Furthermore, the delivery of an antimetabolite (e.g., gemcitabine) is performed under preoperative adjuvant conditions, and It may be initiated in a neoadjuvant situation after surgery. In some embodiments, an antimetabolite ( For example, gemcitabine delivery may be initiated at the time of surgery. In some embodiments, metabolism The delivery of the antagonist (e.g., gemcitabine) is initiated before or after radiation therapy. In some embodiments, the result is obtained by treatment with an antimetabolite (e.g., gemcitabine). The individuals present will not receive radiation therapy.

[0159] In some embodiments, antimetabolite (e.g., gemcitabine) is delivered during cystoscopy. It can be administered to [the patient].

[0160] In some embodiments, this method delays the need for cystectomy. In some embodiments, This method may be used to expand the therapeutic area before cystectomy.

[0161] In some embodiments, the cancer is surgically removed before administration of an antimetabolite (e.g., gemcitabine). In some embodiments, the individual receives an antimetabolite (e.g., gemcitabine) to the bladder. Before administration, undergo TURBT. In some embodiments, there is no visible tumor. The tumor is maximally resected before gemcitabine administration. In some embodiments, the patient , T0 after TURBT. In some embodiments, muscle-invasive bladder cancer in individuals is treated A method comprising the steps of a) excising the tumor, and b) administering a small amount of gemcitabine. A method is provided herein that includes the step of administering a drug locally to the bladder over a 24-hour period. In some embodiments, a method for treating non-muscle-invasive bladder cancer in an individual, a) the step of surgically removing the tumor, and b) administering gemcitabine for at least 24 hours. A method comprising the step of administering a substance locally to the bladder is provided herein. Patient group

[0162] The methods provided herein are useful for treating a certain range of individuals having urothelial carcinoma. For example, in some embodiments, urothelial carcinoma is bladder cancer. Bladder cancer is locally advanced bladder cancer. In some embodiments, bladder cancer is metastatic bladder cancer. It is bladder cancer. In some embodiments, the bladder cancer is muscle-invasive bladder cancer. In some embodiments, bladder cancer is non-muscle-invasive bladder cancer. In some embodiments, bladder cancer is carcinomatous. It is cancer. In some embodiments, bladder cancer is BCG (Calmette-Guérin bacilli) refractory. It is cancer. In some embodiments, bladder cancer is papillary bladder cancer. In some embodiments Bladder cancer is grade 1 / 3, 2 / 3, or 3 / 3. In some embodiments, bladder Bladder cancer is a type of bladder cancer that is classified as stage I, stage II, stage III, or stage IV. Yes. In some embodiments, bladder cancer is high-grade invasive papillary urothelial carcinoma. In some embodiments, the bladder cancer is non-invasive high-grade urothelial carcinoma. In some embodiments, bladder cancer is multifocal, invasive, high-grade papillary urothelial carcinoma. So, bladder cancer is cT2 or cT3. In some embodiments, the bladder is carcinoma in situ. This is cT2.

[0163] In some embodiments, the methods provided herein involve the treatment of an individual having a compromised immune system. This includes the procedure. In some embodiments, the method provided herein involves a low level of checkpoint Individuals with an inhibitor of an inhibitor (checkpoint inhibitor), for example, low This includes treatment of individuals having expression of PD-L1 and / or PD-1. In some embodiments, The method provided herein involves transporting low, intermediate, or high levels of nucleoside transporters. This includes the treatment of patients having the condition. In some of these embodiments, the nucleoside transporter is hENT In some embodiments, the methods provided herein are for individuals having cytopenia. This includes treatment. In some embodiments, the method provided herein involves a patient who has previously received chemotherapy. This includes treatment of the individual. In some embodiments, the methods provided herein are immunomodulatory therapies. This includes the treatment of individuals that are unsuitable.

[0164] In some embodiments, individuals who are not eligible for neoadjuvant cisplatin-based treatment are used. A method for treating bladder cancer (e.g., MIBC), wherein an antimetabolite (e.g., A method comprising the step of locally administering gemcitabine to the bladder is provided herein. In some embodiments, for individuals who refuse neoadjuvant cisplatin-based treatment... A method for treating bladder cancer (e.g., MIBC), comprising an antimetabolite (e.g., ge A method comprising the step of locally administering mucitabine to the bladder is provided herein. In some embodiments, the patient has a cT2 disease with high-risk characteristics, such as lymphatic infiltration (LV). I) Bladder cancer in individuals without hydronephrosis and associated carcinoma in situ (CIS) (for example) A method for treating MIBC, wherein an antimetabolite (e.g., gemcitabine) is administered to the bladder. A method comprising the step of administering locally is provided herein. In some embodiments, He is willing to undergo radical cystectomy, but is not receiving cisplatin-based neoadjuvant therapy. A method for treating bladder cancer (e.g., MIBC) in individuals who are unsuitable for the treatment, A method comprising the step of locally administering an anti-antagonist substance (e.g., gemcitabine) to the bladder, Provided herein. In some of these embodiments, the individual has a cT2 cancer. In some embodiments, the individual has cT2 muscle-invasive bladder cancer. The antimetabolite is delivered locally to the individual's bladder for at least 24 hours. In one embodiment, an antimetabolite (e.g., gemcitabine) is administered to an individual over a period of 7 days. It is delivered locally to the bladder. In some of these embodiments, 225 mg of gemcitabine is It is delivered locally to the bladder over a period of 7 days. In some of these embodiments, this method is used. The procedure involves the local delivery of 225 mg of gemcitabine to the bladder over 7 days, followed by... A 14-day drug-free period followed by 225 mg of gemcitabine administered to the bladder over 7 days. The method includes the step of delivering to the location. In some embodiments, this method is used to deliver an antimetabolite (e.g. The procedure includes the step of delivering gemcitabine (or similar) topically to the bladder over a period of three weeks. In one embodiment, this method involves locally delivering 225 mg of gemcitabine to the bladder over a period of three weeks. The method includes the step of reaching [a certain point]. In some embodiments, this method involves administering 450 mg of gemcitabine The procedure includes a step of local delivery to the bladder over a period of six weeks. In some embodiments, an antimetabolite is used. The substance is gemcitabine.

[0165] In some embodiments, the individual has poor general condition, renal dysfunction, hearing loss, peripheral neuropathy and Based on comorbidities, including heart disease, the patient is ineligible for cisplatin-based treatment. Morphologically, individuals may have one or more high-risk features, such as lymphatic infiltration (LVI), Based on the absence of hydronephrosis and associated carcinoma in situ (CIS), cisplatin-based treatment It is unsuitable.

[0166] To date, neoadjuvant therapy followed by radical cystectomy, or removal of the bladder, It was the standard treatment for muscle-invasive bladder cancer. The body attempts to limit the local progression of an untreated or inadequately treated disease, The patient undergoes palliative transurethral resection of bladder tumor (TURBT). This procedure is performed to alleviate hematuria, pain, and It can temporarily manage urgent local symptoms, but it is not used with a curative intention. Therefore In one embodiment, the present invention provides local administration of an antimetabolite (e.g., gemcitabine) to the bladder. By doing so, bladder cancer in individuals who are unsuitable or unqualified for cystectomy ( For example, it provides a method for treating MIBC.

[0167] In some embodiments, bladder cancer of the lower urinary tract in individuals unsuitable for cystectomy (e.g.) For example, a method of treating MIBC, in which an antimetabolite (e.g., gemcitabine) is administered to the bladder A method comprising the step of locally delivering to the bladder is provided herein. In some embodiments This is a method for treating bladder cancer (e.g., MIBC) in individuals who are unsuitable for cystectomy. A method comprising the step of locally administering an antimetabolite (e.g., gemcitabine) to the bladder. Methods including the above are provided herein. In some embodiments, the bladder of a frail individual A method for treating bladder cancer (e.g., MIBC), wherein an antimetabolite (e.g., gemcitabine) A method comprising the step of locally delivering a vial to the bladder is provided herein. In this embodiment, bladder cancer (e.g., MIB) in individuals who cannot undergo radical cystectomy is considered. A method for treating C), wherein an antimetabolite (e.g., gemcitabine) is administered locally to the bladder. A method comprising the step of delivering is provided herein. In some embodiments, the bladder of an individual A method for treating bladder cancer (e.g., MIBC) in an individual without removing the bladder, A method comprising the step of locally delivering an antagonist (e.g., gemcitabine) to the bladder, Provided herein. In some embodiments, individuals who are unsuitable or unqualified for cystectomy are shown. A method for treating bladder cancer (e.g., MIBC) in the body, wherein an antimetabolite (e.g.) A method comprising the step of locally delivering gemcitabine to the bladder is provided herein. In some embodiments, a method for treating bladder cancer (e.g., MIBC) in an individual. A method is provided herein for bladder cancer, which is metastatic bladder cancer. In the embodiment, bladder cancer (e.g., MIBC) in individuals with cT2-cT3 disease is described. A method for treating ) by locally delivering an antimetabolite (e.g., gemcitabine) to the bladder. A method including steps to reach a certain point is provided herein. A method for treating bladder cancer (e.g., MIBC) in an unsuitable individual, wherein a) tumor The steps include a) excising the ulcer and b) locally delivering gemcitabine to the bladder. Methods are also provided herein. In some embodiments, the method is unsuitable for cystectomy. or a method for treating muscle-invasive bladder cancer in an ineligible individual, a) TURB The steps are: a) administering T, and b) administering gemcitabine to the bladder for at least 7 days. A method comprising the step of delivering to a location is provided herein. In some embodiments, Methods for treating muscle-invasive bladder cancer in individuals unsuitable or unqualified for vasectomy. a) the step of performing TURBT, and b) gemcitabine for 7 days to 1 80 days, 7-90 days, 7-60 days, 7-30 days, 7-21 days Alternatively, a method including the step of locally delivering to the bladder over a period of 7 to 14 days is described below. Provided in detail. In some of these embodiments, gemcitabine improves the quality of life of an individual. To improve the condition, it can be delivered chronically to the bladder or continuously throughout the lifespan of the individual. In some embodiments, an antimetabolite (e.g., gemcitabine) is administered for at least 24 hours. It is delivered locally to the individual's bladder. In some embodiments, an antimetabolite (e.g.) Gemcitabine is administered for 24 hours to 3 weeks, 2 to 20 days, 3 to 16 days, or 4 to 14 days. It is delivered locally to the individual's bladder during the process. In some embodiments, an antimetabolite ( For example, gemcitabine is delivered locally to the individual's bladder over a period of 7 days. In some embodiments, 225 mg of gemcitabine is administered locally to the bladder over a period of 7 days. It is delivered to the target. In some of these embodiments, this method delivers 225 mg of gemcitabine. The procedure involves delivering the drug locally to the bladder over a 7-day period, followed by a 14-day drug-free period, and so on. The following step involves delivering 225 mg of gemcitabine topically to the bladder over a period of 7 days. Includes. In some embodiments, this method involves topically administering an antimetabolite to the bladder over a period of three weeks. The method includes the step of delivering 225 mg of gemcitabine. The procedure includes the step of locally delivering the drug to the bladder over a period of three weeks. In some embodiments, This method involves delivering 450 mg of gemcitabine locally to the bladder over a period of 6 weeks. It contains p. In some embodiments, the antimetabolite is gemcitabine.

[0168] In some embodiments, the individual is National Comprehensive Ca Under the NCERN Network (NCCN) guidelines, those who are ineligible for radical cystectomy are... Yes. For example, an individual may be unsuitable for curative treatment due to weakness. In such cases, individuals typically receive palliative radiation without chemotherapy (3.5 Gy / min). (10 treatments per split; or 7 Gy / 7 splits; TURBT; or no treatment). In some embodiments, the organism is unsuitable for platinum-based chemotherapy. Pre-injection chemotherapy is not recommended for the individual. In some embodiments, the individual is curative. No treatment or systemic chemotherapy is received. In some embodiments, the individual has a disease with cT2-cT3. It has.

[0169] In some embodiments, the individual is the American Society of Anest Based on the hesiology (ASA) guidelines, radical cystectomy is not approved. For example, individuals who cannot undergo radical cystectomy require general anesthesia or epidural anesthesia. This could be considered medically unsuitable for such a surgery.

[0170] In other embodiments, the individual is the American Society of Anesth Comprehensive Geriat provided by esiologists As determined by the RIC Assessment, an effective postoperative care infrastructure is needed. Or they may lack personnel. Under these guidelines, individuals are able to perform independent activities of daily life. Abnormalities, severe malnutrition, cognitive impairment, or the Geriatric Medicine Cumulative Disease Assessment Scale (CUMULAT). ive illness rating scale for geriatrics) If a patient exhibits comorbidities of (CISR-G) grade 3-4, they are considered frail.

[0171] The method of the present invention is important and compared to standard treatment regimens that require bladder removal. It also provides significant treatment benefits. The present invention is suitable for cystectomy but undergoes cystectomy. It also has the advantage of being useful as a bladder-preserving protocol for individuals who do not choose to undergo surgery. The present invention provides a method that, compared to currently available treatments, allows the bladder to be treated after bladder cancer. For individuals that may be able to maintain this condition, it results in a significantly improved quality of life. Therefore, in some embodiments, bladder cancer (e.g., MIBC) in an individual is treated. A bladder-preserving method that involves locally delivering an antimetabolite (e.g., gemcitabine) to the bladder. A method comprising the step of reaching is provided herein. In some embodiments, the bladder of an individual A method for treating bladder cancer (e.g., MIBC) without removing an antimetabolite (e.g.) For example, a method comprising the step of locally delivering gemcitabine to the bladder is provided herein. Otherwise, bladder cancer (e.g., MIBC) in individuals undergoing cystectomy will be treated. A method of treatment comprising locally delivering an antimetabolite (e.g., gemcitabine) to the bladder. Methods including the step of cystectomy are also provided herein. In some embodiments, cystectomy Bladder cancer in individuals who are eligible but choose not to undergo treatment (e.g., MIBC) A method for treating ) by locally delivering an antimetabolite (e.g., gemcitabine) to the bladder. A method comprising the steps of achieving a radical bladder is provided herein. In some embodiments, A method of bladder preservation as an alternative to resection, comprising an antimetabolite (e.g., gemcitabine) A method comprising the step of locally delivering ) to the bladder is provided herein. Some implementations Morphologically, bladder cancer in individuals who do not choose to undergo cystectomy (e.g., MIB) A method for treating C), wherein an antimetabolite (e.g., gemcitabine) is administered locally to the bladder. A method comprising the step of delivering is provided herein. In some embodiments, the bladder of an individual A method for preserving the bladder, which involves locally delivering an antimetabolite (e.g., gemcitabine) to the bladder. Methods including the step of reaching a certain point are provided herein. In some embodiments, the bladder is removed. A method for treating bladder cancer (e.g., MIBC) in an individual without using an antimetabolite A method comprising the step of locally delivering a substance (e.g., gemcitabine) to the bladder is described herein. Provided in some embodiments, CT in individuals otherwise undergoing cystectomy 2. A method for treating urothelial carcinoma, wherein an antimetabolite (e.g., gemcitabine) is administered to the individual A method comprising the step of locally delivering to the bladder is provided herein. Some embodiments In this state, an antimetabolite (e.g., gemcitabine) is present in the individual for at least 24 hours. It is delivered locally to the bladder. In some embodiments, an antimetabolite (e.g., gemsitabi) (n) can be used for periods of 24 hours to 3 weeks, 2 to 20 days, 3 to 16 days, or 4 to 14 days. It is then delivered locally to the individual's bladder. In some embodiments, an antimetabolite (e.g.) Gemcitabine is delivered locally to the individual's bladder over a period of 7 days. In some formulations, 225 mg of gemcitabine is delivered locally to the bladder over a period of 7 days. In some of these embodiments, this method involves administering 225 mg of gemcitabine over 7 days. The first step is to deliver the drug locally to the bladder, followed by a 14-day drug-free period, and then 225mg. The procedure includes the step of locally delivering g of gemcitabine to the bladder over a period of 7 days. In terms of administration, this method involves administering an antimetabolite (e.g., gemcitabine) over a period of three weeks. This includes the step of delivering it locally to the bladder. In some embodiments, this method is 225 The procedure includes a step of locally delivering mg of gemcitabine to the bladder over a period of three weeks. Morphologically, this method involves locally administering 450 mg of gemcitabine to the bladder over a period of 6 weeks. The process includes the step of delivering to [the target]. In some embodiments, the antimetabolite is gemcitabine.

[0172] In some embodiments, this method typically involves radical resection followed by neoadjuvant therapy. This method is particularly suitable for treating individuals with CT2 patients. This results in local / regional (local-regional) control of the disease, including the bladder. This method can be used for long-term management in a urinary tract preservation population. This method is suitable for patients who do not experience invasive recurrence. Furthermore, good long-term bladder function and a low rate of salvage cystectomy also occur, and these All of these individuals had an average age of 70 and were elderly and relatively frail, and had bladder cancer. In that regard, it is primarily important. endpoint

[0173] The methods provided herein are useful for treating urothelial carcinoma of the lower urinary tract. In some applications, the methods provided herein result in a reduction in the time to transition. In some embodiments, the methods provided herein prevent transfer. The method provided in this document results in the prevention of metastasis to lymph nodes. In some embodiments, this specification The method described in the book is intended to predict the onset of the disease in the lymph nodes (nodal involvement). To prevent disease. In some embodiments, the methods provided herein, compared to existing treatments, To increase the rational response rate. For example, the method provided herein increases it by about 20%, about 30%, Approximately 40%, 50%, 60%, 70%, 80%, 90%, or 100% of pathologies Achieves a high success rate. In some embodiments, the method provided herein is for cystectomy. This results in individuals that have not been upstaged at that point. In some embodiments, provided herein The methods used include reducing tumor size, or pathological or clinical reduction of the tumor. Taging occurs. In some embodiments, the methods provided herein are used in March 2017. Compared to standard care at the time of the month, there was an increase in clinical complete response (cCR) and partial response (cPR). and / or produce a total response (cOR). In some embodiments, provided herein The method produces a pathological complete response (pCR) or a pathological partial response (pPR). In the embodiment, pPR is performed in the absence of residual invasive cancer and the presence of residual non-muscle-invasive cancer. It is defined as follows. In some embodiments, pCR is residual in the bladder and regional lymph nodes. It is defined as the absence of cancer. In some embodiments, this method is defined as disease-free survival or overall This results in an improvement in survival time. In some embodiments, this method produces a reduction in hematuria. To do.

[0174] In some embodiments, the method provided herein results in the disappearance of muscle-invasive tumors. In some embodiments, the method provided herein involves a procedure in which the histopathological stage is p This results in complete disappearance of muscle-invasive tumors, such as those with a T0 state. In some embodiments, as specified herein The method provided results in the disappearance of muscle-invasive tumors with residual pTis. Morphologically, the methods provided herein do not result in residual lateral proliferative tumors. Some implementations In this state, the method provided herein results in a clear reduction in tumor volume. In embodiments, the method provided herein results in tumor reduction. II. Intravesical (intravesical) devices Device shape

[0175] In some embodiments, the methods provided herein use an intravesical (intravesical) device This includes administering an antimetabolite (such as gemcitabine) using the method. In some embodiments, Intravesical (intravesical) devices include deployment and retention configurations. For example, The chair is relatively straight, suitable for insertion into the bladder of an individual through a lumen (e.g., the urethra). In other words, the unrolled shape (deployment shape) and the shape that holds the device inside the bladder It may be elastically deformable between a suitable holding shape and a suitable holding shape. For the purposes of this disclosure, Examples include "relatively widened shape," "relatively high profile shape," or "retaining shape." The term generally refers to a suitable pre-installed device for holding a device inside the bladder, although this is not the only one that is suitable for this purpose. Snatzel shape or other coil shapes (e.g., bi-oval or overlapping coils) Any shape suitable for holding the device in the intended implantation position, including (including the ) The retaining shape is such that the device is drawn into the urine when the individual urinates and is not excreted. To avoid this. Similarly, "relatively low profile shape" or "deployment shape" These terms are not limited to these, but also refer to other catheters, cystoscopes, or other devices placed in the urethra. To deploy devices through the working channel of the deployment device Deploying drug delivery devices to the body, such as the bladder, including suitable linear or elongated shapes. Any shape suitable for mentation is generally shown. In the embodiment, the drug delivery device is It can naturally take on a relatively expanded shape, and can be applied to the body manually or using external devices. It may be deformed into a relatively low profile shape for insertion. For example, external devices may be An inserter configured for urethral insertion may be an intravesical (intravesical) device. When deployed, the first relatively wide area for physical retention occurs spontaneously or naturally. It returns to its original shape. In some embodiments, the device behaves like a spring and compresses under load. It deforms in response to (for example, the device deforms to the deployment shape), but the load is removed When removed, it spontaneously returns to its retained shape.

[0176] In some embodiments, the shape of the intravesical (intravesical) device described in the previous paragraph The change function is identified above and disclosed in the patent application publication incorporated herein by reference. By including a shape-retaining frame (i.e., a "retaining frame") for objects within the device, It may be provided as such. In some embodiments, the device is an elastic wire, for example, Nichino The retaining frame may be made of a superelastic alloy such as 1800, and includes a retaining frame lumen to which the retaining frame is fixed. The retaining frame is a "pretzel" such as those disclosed in previously incorporated applications. It may be configured to spontaneously return to a retaining shape such as a "L" shape or another coil shape. Furthermore, the retaining frame can hold the device in the body, such as in the bladder. The retaining shape is designed to allow the individual to... The device is designed to prevent it from being drawn into the urine and excreted during urination. For example, to prevent it from being retained. The frame allows the device to be introduced into the body with a relatively low profile shape. Furthermore, the device is designed to return to its relatively expanded shape within the body, and to allow the detrusor muscle to contract. In response to expected forces such as fluid forces associated with urination, the device moves to a relatively low position within the body. It may have elastic limits and moduli that prevent it from taking on a rophilic shape. When deployed, it limits or prevents accidental discharge and retains within the individual's bladder. It is possible.

[0177] In some other embodiments, the shape-changing function of the intravesical (intravesical) device is provided by the device Shape the wozing with at least partially thermoformable elastic polymer. It can be provided by doing so.

[0178] The material used to form the device body (i.e., housing) is Depro The device is at least partially elastic so that it can move between the component and the retaining shape. or may be flexible. If the device is in a retaining shape, the retaining frame portion is shown. As such, it tends to be placed in the drug reservoir section, but in other cases the retaining frame section The drug reservoir may be located inside, outside, above, or below the device body. The material used to form the y may be water permeable, and therefore the solubilizing liquid (e.g.) For example, urine is contained in the drug reservoir once the device is deployed in the bladder. Non-metabolites, immunomodulatory agents, additional therapeutic agents, functional agents, or combinations thereof The drug can enter the reservoir portion to solubilize the liquid form. For example, silicone or Other biocompatible elastomer materials may be used. In other embodiments, the device body The D may be formed, at least partially, from a water-impermeable material.

[0179] In some embodiments, the device body is made of an elastic, biocompatible polymer material. The material may be non-absorbent or absorbent. An example of a non-absorbent material is poly(A Poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone(py) Poly(vinyl acetate), poly(urethane), cellulose, cellulose Suacetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene) ) and other fluorinated polymers, as well as synthetic polymers selected from poly(siloxane) Examples include absorbent materials, specifically biodegradable or biodegradable polymers. Poly(amide), poly(ester), poly(esteramide), poly(acid anhydride), poly Poly(orthoester), polyphosphazene, pseudopoly(amino acid), poly(glycerol) Poly(glycolic acid), poly(glycolic acid), poly(glycolic acid), poly(glycolic acid-co-glycolic acid) Caprolic acid, poly(caprolactone), poly(caprolactone) (PC) derivative, amino acid Alcohol-based poly(esteramide) (PEA) and poly(octane citrate-diodeoxycholic acid) Synthetic polymer selected from (POC) and other curable bioabsorbable elastomers - is one example. PC-based polymers are lysine diiso to obtain elastomeric properties. Additional ingredients such as cinanate or 2,2-bis(e-caprolactone-4-yl)propane A crosslinking binder may be required. Copolymers, mixtures, and combinations of the above materials are also used. It's okay to do that.

[0180] In some embodiments, the device body is made of silicone, thermoplastic polyurethane, or ethylene. Includes vinyl acetate (EVA) or a combination thereof. In some embodiments, The vice body contains two different thermoplastic materials, one of which is hydrophilic thermoplastic poly Urethane is drug-permeable, while the other is drug-impermeable. Drug-impermeable materials are hydrophilic. Selected from the group consisting of polyurethane, hydrophilic polyester, and hydrophilic polyamide. i. The device body uses one or more of these materials, U.S. Patent Publication No. 2 As described in issue 016 / 0310715, annular formations formed by extrusion or co-extrusion processes. It may include a tube. Drug core

[0181] In embodiments in which antimetabolites are delivered from an intravesical (intravesical) drug delivery device, the drug The object depends on a specific mechanism by which the device controls the release of drugs into the fluid in the bladder (e.g., urine). It may be contained in the device in various forms. In some embodiments, the drug is advantageous This can facilitate the stable storage of drugs before the device is used, and is advantageous for the stored devices. The drug payload is smaller than what is possible when the drug is contained in the form of a liquid solution. It is provided in a solid, semi-solid, or other non-liquid form that can be stored by volume. In one embodiment, the non-liquid form is a tablet, granules, powder, or semi-solid (e.g., ointment, cream). A selection is made from a preparation (paste or gel), capsules, and combinations thereof. In terms of form, the drug is a multi-tablet form, such as the minitablet described in U.S. Patent No. 8,343,516. It is in the form of...

[0182] For example, antimetabolites are used in suspensions, solutions, or emulsions in oily or aqueous vehicles. It may take any form and may contain formulation agents such as suspending agents, stabilizers and / or dispersants. It is permissible to do so. Alternatively, the active ingredient may be placed in a suitable vehicle before use, e.g., a sterilized vehicle free of pyrogens. For compositions using water, sterile isolation of sterile solids or freeze-drying from solutions is performed. It can be in the form of a powder obtained in this way.

[0183] In one embodiment, the antimetabolite is released from the release aperture of the device housing. Formulated using one or more excipients, including a viscosity enhancer for sustained release of antimetabolites. In another embodiment, the device reservoir contains both antimetabolites and viscosity enhancers. This includes methods, but they are not co-formulated; instead, they are contained within separate regions within the reservoir, for example. It is supplied as separate tablets. This is not the only example, but polyethylene oxide (PEO) is also used. Suitable viscosity enhancers to be included are known in the pharmaceutical field. In some modifications of the embodiments... The viscosity enhancer may be provided together with urea or another penetrating agent, for example, in the form of a formulation.

[0184] In one embodiment, the antimetabolite is administered to the individual together with a solubility enhancer. In this case, the solubility enhancer is urea. In one embodiment, urea is in tablet or other solid form. Provided and combined with an antimetabolite in the drug reservoir of an intravesical (intravesical) drug delivery device. It is loaded into the device. Urea promotes the generation of osmotic pressure in the drug reservoir, depending on the device. It may also function as a penetrating agent. In certain embodiments, it functions as an antimetabolite and a penetrating agent. This is incorporated herein by reference as PCT WO2015 / 026813 (Lee et al.). As described in ), separate tablets (or) located in different areas of the drug reservoir It is composed of other solid forms.

[0185] In some embodiments, the device may include a drug reservoir lumen. In some cases, each drug reservoir lumen contains one or more drug tablets or other solids. The device may hold a drug unit. In one embodiment, the device may hold several separate drug units. The tubular lumen holds approximately 10 to 100 cylindrical drug tablets, such as mini tablets. In this embodiment, the mini tablets are approximately 1.0 to 3.3 mm in size, such as approximately 1.5 to 3.1 mm. They have a diameter and a length of approximately 1.5 to 4.7 mm, such as approximately 2.0 to 4.5 mm. obtain. Drug Housing

[0186] The release of antimetabolites from intravesical (intravesical) devices described herein may differ from that described herein. It may be driven and controlled by a mechanism of action. In various embodiments, the drug is a drug house. Diffusion through the walls of the drug housing can cause one or more designated areas of the walls of the drug housing to be affected. By diffusion through the aperture, by osmotic pressure through the aperture of the drug housing , osmotic pressure through one or more transiently formed microchannels, bladder Erosion of drug formulations by contact with urine in the bladder, or by a combination of these, can occur in the bladder cavity. (Intravesical) drug delivery device may release the drug. In some embodiments, drug release is performed by Drug-permeable polymer or matrix component defining part of the vice housing It is controlled by drug diffusion through a drug permeable polymer. In one embodiment, the device is a drug permeable polymer —Includes components.

[0187] The size of the housing, including the thickness of the walls, is particularly important for the drugs (and functional agents) contained within. (In this case) the volume of the formulation (one or more), and drug delivery from the device body / housing. The desired speed, the intended site for device implantation in the body, and the desired mechanical properties of the device. Integrity, desired release rate or permeability into water and urine, desired induction time before the start of the first release The interval and the desired method or route of insertion into the body may be selected. In embodiments where the tube is present, a tube wall that is too thin does not have sufficient mechanical integrity. While this may be possible, an overly thick tube wall is undesirable for initial drug release from the device. It may take a long induction time and / or the urethra or other narrow body lumen. Because it may not have sufficient flexibility to enable delivery through the tube, The wall thickness may be determined based on the mechanical properties and water permeability of the tube material.

[0188] In some embodiments, the housing is an elongated annular tube having an inner diameter of approximately 2 mm to 5 mm. It may be a tube. The drug, and in some cases the functional agent, has an inner diameter of an elongated annular tube and The solid tablets may have substantially the same diameter. In some embodiments, the housing is One or more first drug units containing a drug, and a functional agent that facilitates the release of the drug. It holds one or more second drug units containing the agent. One of the first unit tablets Alternatively, multiple units may be used to fill the lumen of the tube to a length of approximately 1 cm to 3 cm, and the second unit One or more tablets are filled into the lumen of the tube, which is approximately 10 cm to 15 cm long. Good. In one embodiment, the capacity of the first unit (one or more) versus the second unit (single The ratio of the volume of a number (or more) is approximately 0.05 to 0.5. Other lengths of tablet payloads The ratio will also be considered.

[0189] In some embodiments, the housing has a wall thickness of 0.1 to 0.4 mm, such as a wall thickness of 0.2 mm. It may be an elongated annular tube. The housing material is one or more biocompatible materials. It may contain a ferrous elastomer. The housing material is 25A, 50A, 65A Selected to have a durometer of 25A to 80A, such as 70A or 80A. good.

[0190] In various embodiments, the intravesical (intravesical) device is used in the method provided herein. The therapeutically effective concentration of the drug in the urine of the bladder is maintained as described above. The drug can be released continuously or intermittently to achieve a certain concentration. For example, 1 hour to 1 month This can last for periods such as a month, 2 hours to 2 weeks, 6 hours to 1 week, or 24 hours to 72 hours. In certain embodiments, the intravesical (intravesical) device delivers an antimetabolite at a dose of 1 mg / day. 1000mg / day, for example, 20mg / day to 300mg / day or 25mg / day to 300mg / day It can be released in amounts of g / day. In certain embodiments, these release rates are not specified herein. They are provided over the specified treatment period. In certain embodiments, these release rates are It is provided over a treatment period of 14 to 21 days. Penetration and diffusion systems

[0191] Following in vivo deployment, the device releases the drug, as described above. The release occurs due to the osmotic pressure gradient between the inside and outside of the device, and the drug in the device under osmotic pressure. Emissions can occur when an object passes through one or more openings or passage pores. This can also occur by diffusion, thereby discharging the drug through one or more openings in the device. The drug concentration gradient between the inside and outside of the device and / or through the passage pore. The drug passes through the drug-permeable wall of the device. A combination of these release modes within a single device. This is possible, and in some embodiments, the overall approach is not easily achieved in any of the individual forms. This is preferable for achieving a suitable drug release profile.

[0192] In some embodiments where the device contains the drug in a solid form, the elution of the drug from the device is This occurs following the dissolution of the drug within the device. Body fluids enter the device, come into contact with the drug, and the drug The drug is solubilized, and then the dissolved drug diffuses from the device, or under osmotic pressure or It flows from the device via diffusion. For example, a drug is deployed in the bladder by the device. If so, it may be solubilized by contact with urine. In a particular embodiment, the housing The water-permeable wall portion allows the solubilized drug in the aqueous solution to be released through the wall portion. It is permeable to water, also referred to herein as "transwall diffusion." After the device is implanted, water Alternatively, urine permeates through the wall and enters the reservoir, dissolving functional agents and / or drugs. The drug is then controlled by the drug concentration gradient between the inside and outside of the device. It diffuses directly through the wall at a high speed. For example, housing and / or any water or The drug-permeable wall portion is made of silicone, thermoplastic polyurethane, and ethylene-co-vinyl acetate. It may be tate (EVA), or a combination of these.

[0193] In some embodiments, the intravesical (intravesical) device contains 225 mg of gemcitabine. It can contain a concentration of 1.5. In some of these embodiments, the device also over a period of 7 days. For three weeks, the individual receives approximately 100 to 225 mg of gemcitabine (for example, approximately 140 mg). (mg, approximately 160mg, approximately 180mg, approximately 200mg or approximately 220mg) antimetabolite m It may be configured to deliver g.

[0194] In certain embodiments, drug delivery devices are both described herein by reference in their entirety. Incorporated WO2014 / 145638 and U.S. Patent Publication 2016 / 031071 It may include a permeation system as described in item 5. In some embodiments, a drug delivery device This is a closed drug reservoir lumen, bounded by a first wall structure and a hydrophilic second wall structure. ; and a drug formulation having an antimetabolite contained in the lumen of the drug reservoir. Including a zing, the first wall structure is permeable or impermeable to water and impermeable to drugs. It is transient, and the second wall structure is permeable to antimetabolites.

[0195] In some embodiments, the device housing serves as a first wall structure. A device made from the material and a second material that serves as a second wall structure. It has a wall that serves as the boundary of the drug reservoir and defines it, thereby drug release is based Essentially, it occurs only through the second material. In one embodiment, the device includes an aperture. First, drug release occurs solely by diffusion through the second wall structure. The terms "impermeable to drugs" and "impermeable to water" refer to the period of release of the drug. Therefore, drugs or water are not essentially released through the wall structure, effectively preventing the release of drugs or water. It refers to a wall structure that is impermeable to the bladder. For use in the bladder, it is intended to minimize discomfort and irritation to the patient. The device is designed to respond to detrusor contraction in order to avoid or mitigate it (i.e., easy A flexible, soft feel is desirable. Therefore, the first and second materials of the structure Durometer is a design consideration, and the proportion of high-durometer material is related to bladder compatibility. In constructing a device housing of a given size while maintaining the appropriate parameters, This can happen. For example, if the silicone tube has a Shore hardness of 50A to 70A. However, Tecophilic (trademark) thermoplastic polyurethane (Lubrizol C ORP. may have a Shore hardness greater than 70A, such as 80A to 65D. Therefore, rather than fabricating the entire device from a second material that is water-swellable, hydrophilic, and drug-permeable... Utilizing a combination of these two different polymer materials can be advantageous in some cases.

[0196] The arrangement of the first and second wall structures may take various forms. In a particular embodiment, The first wall structure is a cylindrical tube, and the second wall structure is at least one of the cylindrical tubes It is an end wall located at the end of one side, or the first wall structure and the second wall structure are adjacent to each other. Together, they form a cylindrical tube. In other words, drug release occurs through a closed device housing. This is controlled by drug diffusion through drug permeability components that define the portion. The permeable wall structure is positioned to provide a desired rate of controlled drug diffusion from the device. It can be defined, its dimensions determined, and its material properties determined. In one embodiment, the drug-permeable wall is Optionally, an inner washer and an outer washer are placed inside the lumen of the tube at or near the end of the tube. The stabilized disc may be sandwiched between the side washers. Another implementation Morphologically, the drug-permeable wall is part of the side wall of the tubular housing, or the end of the tubular housing. It is part of the end plug, positioned as such.

[0197] The length and width, for example, the wall portion formed of a water-permeable material, are determined by the device housing. Selected to provide a desired speed of water flow to the reservoir as defined by [the specified method]. Therefore, the width of the water-permeable wall portion is the angle of the arc that defines the wall when viewed in a cross-section perpendicular to the lumen axis. It is quantified by the following: The water permeable area(s) of the device housing is permeable. A more suitable biocompatible environment is provided to result in a selected area and therefore a faster rate of water leaching. To favorably maintain the preferred overall dimensions and elasticity of devices formed with a lastomer. It may be controlled. Advantageously, the device housing can be formed by a co-extrusion process. The structural diversity of the water permeable region (one or more) depends on the selection of processing parameters. This can be created using conventional co-extrusion equipment, thereby enabling the creation of three-dimensional devices with multiple structures. It provides a beneficial ability to manufacture the configuration cost-effectively. In some embodiments, a water-permeable region The length (singular or plural) extends only a portion of the total length of the device. Such embodiments Therefore, while maintaining a desired rate of drug release over a long period of time, A larger arc angle of the water-permeable region(s) may be used.

[0198] In some embodiments, the wall may have varying thicknesses along its perimeter, for example, a drug The permeable portion may have a thickness thinner than the drug-impermeable portion. Furthermore, even thinner drug The permeable wall structure is positioned at various locations relative to the adjacent, thicker drug-impermeable wall structure. In some embodiments, drug release defines a portion of the closed device housing. It is controlled by drug diffusion through drug permeability components. The drug permeability wall structure is Positioned to provide a desired rate of controlled drug diffusion from the device, and dimensions It can be determined and possess material properties.

[0199] In some embodiments, drug delivery devices are adjacent to each other and together form a drug reservoir lumen. A housing including a first wall structure and a second wall structure that form a tube defining a tubing; The drug contains the drug contained in the lumen of the drug reservoir, (i) a second wall structure or the first Both the wall structure and the second wall structure are permeable to water, (ii) the drug enters the second wall The first wall structure is designed to allow for in vivo release through diffusion via the structure of the drug. (iii) The second wall structure is impermeable to drugs, and the second wall structure is permeable to drugs. The wall structure is a cross-section perpendicular to the long axis of the tube, covering 90 percent of the tube's cross-sectional area. (iv) and the first wall structure, which account for less than 100%, comprise the first polyurethane composition.

[0200] In some embodiments, the device extends between the first closed end and the second closed end. A drug reservoir lumen; and an elongated bullet containing the drug contained in the drug reservoir lumen. (i) The housing includes a waterproof housing, and the housing is made of a first material that is impermeable to drugs. A first cyclic segment in which the body is formed, and a second material that is permeable to drugs. It is formed at least partially from the second material in the second annular segment A second cyclic segment configured to release the drug in vivo by diffusion (ii) including a tubular wall structure, and (ii) the first annular segment is formed integrally with the It has a first end connected to the first end of two annular segments.

[0201] In some embodiments, the walls defining the drug reservoir lumen may have varying thicknesses. A housing with walls of different thicknesses can improve the flexibility, compressibility, or both of the housing. Different wall thicknesses help to secure solid drug units within the drug reservoir lumen. In some cases, it may be the case.

[0202] In some embodiments, the intravesical (intravesical) device body or housing is assembled During the preparation process, an opening is required to seal the drug payload after loading it into the drug reservoir. It may include a discharge section (for example, at the opposite end of the annular tube). Integrated housing and Open or end portions of these provisions of the housing, including modular housing units. Either of these may be sealed to close the opening, if desired. This seal is a sealed object This may be achieved using quality or structure. The sealing structure may be made of metal such as stainless steel, in particular. Polymers such as ricone, ceramics or sapphires or adhesives or these It may be formed from biocompatible materials including combinations. The sealing material or structure is biodegradable or It may be biodegradable. In one embodiment, a medical-grade silicone adhesive or Other adhesives are loaded into the opening in liquid or effective form, and then the housing is opened. It hardens inside to seal the part. In some embodiments, the housing is the device or These include one or more predefined apertures for the release of the drugs. The drug release aperture is not a sealed, defined opening. In other embodiments, the housing The ing does not contain a pre-defined drug release aperture.

[0203] In some embodiments, the device has a predetermined drug release aperture (i.e., open Drugs are released without using the mouth. The release of the drug from the chair may be driven by diffusion or osmosis. Examples of “non-opening” discharge systems are incorporated herein by reference in the PCT patent application publication. U.S. Patent Application Publication No. WO2014 / 144066 (TB130) and U.S. Patent Application Publication No. 2014 / It is listed in item 0276636 (TB134).

[0204] In certain embodiments, the drug delivery device is incorporated by reference herein by US Patent Published by U.S. Patent Publication No. 2016 / 0199544, U.S. Patent No. 8,679,094, and U.S. Patent This may include the infiltration system described in Publication No. 2016 / 0008271.

[0205] In some embodiments, the device comprises a housing defining a reservoir; and a drug containing a The first unit contained within the reservoir; and the in vivo drug from the housing. A functional agent that promotes release is contained within the reservoir at a location separate from the first unit. Includes a second unit which is performed. In some embodiments, the first unit is at least one Contains one or more solid tablets containing a drug (e.g., an antimetabolite such as gemcitabine). The second unit contains one or more solid tablets (for example, containing a penetrating agent such as urea). Includes. In some embodiments, the housing includes all solid locks of the first and second units. An elongated elastomer having a lumen (i.e., reservoir) in which the agent is arranged and contained. It is in the form of a tube. The diameter of the solid tablet may be substantially the same as the diameter of the lumen.

[0206] If osmotic release is the desired drug release mode, the functional agent in the second unit is the drug It may contain a penetrating agent that promotes osmotic release. For example, the penetrating agent may solubilize and / or Alternatively, it may have a higher solubility than the drug to promote the subsequent release of the drug. This is due to the osmotic flow. From delivery-based devices, low-solubility substances that are typically delivered only by diffusion, or It facilitates the delivery of other drugs. The device has sufficient capacity to achieve an osmotic gradient. A certain amount of the functional drug and / or medication may exhibit an induction phase during which it is solubilized.

[0207] Next, the device exhibits a reduced, non-zero emission rate over the decay period, following a long-term zero-order emission rate. It may exhibit a zero-order emission velocity. The desired delivery velocity is not limited to these, but water permeability Surface area and thickness of the wall; water permeability of the material used to form the wall; Shape, size, number and arrangement of chars; as well as dissolution profiles of drugs and functional agents. This can be achieved by controlling / selecting various device parameters, including the . Cut.

[0208] The devices described herein are transmitted via diffusion, either alone or in combination with permeation release. The device may be configured to release the drug. The solubilized drug is housed in the housing. Configured to allow passage through part or one or more apertures good.

[0209] Alternatively, or combined with a water-permeable wall section, the housing allows for in vivo retrieval. It may include at least one aperture configured to allow liquid to enter the bar. The housing is configured to allow the solubilized drug to pass through it, one or more Apertures or passage pores may also be included.

[0210] In some embodiments of the infiltration system, the device housing is a first water-permeable It comprises an elastomer material and a second water-impermeable elastomer material, and both materials are The material is selected to be impermeable to drugs contained in the worming.

[0211] Figures 8A-8C show an embodiment of an intravesical device useful in the method described herein. The following is an example of the configuration. Device 100 consists of a drug reservoir portion 102 and a retaining frame portion 10 Includes 4. In Figure 8A, device 100 is relative to the individual's bladder, suitable for retention within the bladder. It is shown in a widened shape. In Figure 8C, the device 100 is, for example, directed to the patient's urethra. and for passing through it, as well as for insertion into the bladder, such as a cystoscope or other catheter. For deployment via the working channel 202 of the deployment device 200 It is shown with a relatively low profile shape. Deployment to the bladder (device discharge) Following this, device 100 is relatively wide for holding the drug delivery device in the bladder. It can take on a shape. In the illustrated embodiment, the drug reservoir of the drug delivery device 100 The bar and retaining frame portions 102 and 104 are aligned along the long axis and formed as a single unit. Or, they are connected to each other over their respective lengths.

[0212] The drug delivery device 100 includes a drug reservoir lumen 108 and a retaining frame lumen 110. Includes an elastic or flexible device body 106 that defines a drug reservoir lumen 108. This is in the form of a plurality of solid drug units 112 to form a drug reservoir portion 102. It is configured to contain a drug (e.g., an antimetabolite). Adjacent drug unit The gaps 116 or cracks formed between the 112 allow the drug tablets 112 to move relative to each other. This allows the device 100 to operate even when the drug is loaded in solid form. It is flexible. The retaining frame lumen 110 forms the retaining frame portion 104. It is configured to house the retaining frame 114.

[0213] As shown in the cross-sectional view in Figure 8B, the device body 106 is located in the drug reservoir lumen 108 A tube or wall 122 defining the retaining frame lumen 110, and a tube defining the retaining frame lumen 110. or including wall 124. Tubes 122, 124 and lumens 108, 110 are substantially It is cylindrical, and the drug reservoir lumen 108 is relatively larger than the retaining frame lumen 110. It may have a diameter, but other stereochemical configurations may include, for example, the amount of drug delivered, the retaining frame. The selection is based on deployment considerations such as the diameter of the device and the inner diameter of the deployment equipment. It may be selected. The device body 106 is integrally formed by molding or extrusion, etc. However, separate construction and assembly of tubes 122 and 124 is possible. The wall 124 defining the lumen 110 is the entire wall 122 defining the drug reservoir lumen 108. It may be extended along the length, and therefore, as shown, the retaining frame lumen 110 is drug residing It has the same length as the tubular lumen 108, but in other embodiments, one wall is shorter than the other wall. It is not necessary. Furthermore, intermittent bonding may be used, but in the exemplary embodiment, two walls Sections 122 and 124 are bonded along the entire length of the device.

[0214] As shown in Figure 8A, the drug reservoir lumen 108 contains several drug units arranged in series. 112 is loaded. For example, drug units 112 between approximately 20 and 80 units. Approximately 10 to 100 drug units 112 may be loaded. For example, it may be a tablet, beads, or capsule. Essentially any number of drug units. However, depending on the size of the reservoir and drug unit, it may be used. Drug reservoir tube Lumen 108 is a relatively circular open portion at the opposite end of the drug reservoir lumen 108. Includes the indicated open ends 130 and 132. At least one of the open ends is a low-profile device. The transfer of the drug unit 112, which is placed in the drug reservoir lumen 108 during assembly. To bring in.

[0215] The end plug 120 opens the openings 130 and 132 after the drug unit 112 has been loaded. To seal. The end plug 120 may be cylindrical and may be made by friction contact and / or adhesive. Each end plug 1 may be fixed to the drug reservoir lumen 108 by other means of fixation. 20 provides a passage for releasing the drug from the drug reservoir lumen 108, as illustrated. Includes aperture 118 for serving. In some alternative embodiments, 1 end plug Only one includes an aperture. In some other alternative embodiments, none of the end plugs are included. Without an aperture, in some of these embodiments, the tube wall 122 is through Includes a prescribed aperture for the release of the drug.

[0216] The retaining frame lumen 110 has a rigid (thermally) shape in the overlapping coil shape shown in Figure 8A. The retaining frame 114 may be an elastic wire such as a nitrinol wire, The retaining frame 114 holds the device 100 in a relatively low profile shape. This allows the device 100 to be introduced into the body, and it returns to a relatively expanded shape within the body. To enable this, and in response to expected forces such as the contraction of the detrusor muscle and the fluid forces associated with urination. Elastic limits and elasticity prevent the device from adopting a relatively low profile shape within the body. It may have a sex rate. Erosion-based system

[0217] In some embodiments where tablets containing low-solubility drugs are used, the drug is applied to the tablet surface. It is supplied in the form of a tablet that is exposed and fixed to a device, and as a result, U.S. 9,107, As described in Issue 816, drug release from the device is achieved through controlled erosion / dissolution. In some embodiments, the device may include a modular housing. A single-wall housing is typically formed from at least two separate housing units. Each unit contains at least one solid drug unit. The material forming the structure includes at least one drug reservoir lumen capable of accommodating solid drug units. The drug reservoir lumen may have one or more specified openings. For example, The drug reservoir lumen corresponds to at least one solid drug unit contained therein. It may have two opposing openings that expose the opposite end surface. In terms of configuration, at least two separate housing units in the modular housing are, It is connected directly or indirectly by a retaining frame. In some embodiments, the module The ring-type housing unit holds the frame to form a "bracelet" design. It may be placed on top. The device may be one housing unit or multiple housing units. It may have a set. The number of housing units depends on the size of the retaining frame to which they are connected. It can only be limited by Z.

[0218] In some embodiments, one or more separate housing units share a retaining frame. The hose includes a retaining frame tubular lumen through which it is extended. In a particular embodiment, each hose The retaining frame lumen and drug reservoir lumen of the sing unit are arranged parallel to each other. In certain embodiments, each housing unit has a retaining frame lumen and drug reservoir. The tubular lumens are arranged perpendicular to each other. In a further embodiment, each housing unit The lumen of the retaining frame and drug reservoir are 5, 10, 30, 45, 60, and They are positioned at angles other than 0° (parallel) and 90° (perpendicular), such as 85°. In an embodiment described herein, the device has the following three-dimensional arrangement: (1) retaining frame (2) The lumen and drug reservoir lumen are arranged substantially parallel to each other, The lumens of the tubular cavity and the drug reservoir tubular cavity are arranged substantially perpendicular to each other, and ( 3) The retaining frame lumen and drug reservoir lumen are at 0° (parallel) and 90° (perpendicular). Two or more housings, including at least two that are positioned at an outward angle. Includes a unit. Integrated silicone drug delivery system

[0219] In some embodiments, the device is incorporated herein by reference in its entirety. It may contain an elastic polymer drug matrix as described in 2015 / 200752. Device including multiple emission parts

[0220] In certain embodiments, the device includes at least two drug-releasing portions, and the whole As described in WO2011 / 031855 incorporated herein by reference, at least Another release portion releases the drug at a different rate than the other release portion. The release portion, in particular, By having different stereochemical configurations, by accommodating different drug formulations, By using different release mechanisms or combinations thereof, different release rates can be achieved. Yes, it is possible. The emission components may be combined to achieve the desired emission profile. Example For example, the device exhibits different induction or delay times, particularly before the start of the initial emission. After initiation, release the drug according to different rates or different release curves, or drug loading Releasing drugs over different periods of time until they are effectively depleted, or these It may include a combination of release components. Different release components may constitute the overall drug delivery device. The desired release profile from, for example, showing a relatively short initial delay time, followed by a long-term release. To achieve an emission profile that shows sustained emission at a relatively constant rate over time. It can be combined with this.

[0221] In some embodiments, the device may be smaller in size than a conventional drug tablet. The drug is loaded in the form of several solid drug tablets. The device releases the drug into the body. Because it controls drug release, the drug itself contains little to no excipients that control drug release. It is not necessary. Instead, the excipients present in drug tablets are mainly or entirely used during the tableting process. Alternatively, it may be present to promote solubilization in vivo. Therefore, the device It can deliver high drug payloads on a volume or weight basis, and furthermore, the device is minimally invasive. It can be small enough for in vivo deployment using a limited method.

[0222] The drug housing is in liquid or semi-solid form following implantation or in vivo solubilization. It also allows for the release (egress) of the drug. The wall, along its entire length, allows the drug housing to pass through. The wall may be formed from a drug-permeable material that allows for drug leakage. Depending on the drug form, it may be formed from a material that is semipermeable to the drug. For example, the wall is It may be permeable to the drug in one form, such as a charged form, but it may be permeable to the drug in another form, such as an uncharged form. This is not necessary in the form (e.g., base form vs. salt form). The wall is the drug housing. One or more openings or passages formed that completely penetrate the wall, allowing exit from there. It may include.

[0223] The drug housings are aligned in series within the drug housing, on the opposite side of the drug housing. The drug is sealed within the drug housing using a sealing structure such as a plug that closes the entry opening at the end. It contains drugs in the form of several solid drug tablets. Formed between adjacent drug tablets. The gaps or cracks created allow the drug tablets to move relative to each other, and therefore The vice is flexible despite being loaded with drugs in a solid form.

[0224] The drug portion may have any combination of the features or stereoconfigurations described herein. Aperture is provided, omitted, replaced with a pass-through pore, or an additional aperture or The through pores are reinforced; the housing can be an open-cell or closed-cell structure. It may include having a porous wall; one or more decomposable timing structures or release control structures The term "construction" may include a housing, or any combination thereof.

[0225] The drug tablets are arranged in any configuration other than series arrangement, depending on the three-dimensional arrangement of the drug housing. It is acceptable. The drug tablet is any part of the drug housing, not the entire drug housing as exemplified. It may be filled in minutes. Fillers such as silicone adhesives may not be used when drug tablets are not loaded. It may be used by filling any part of the drug housing, and air may be used. The buoyancy of the device is increased. The composition of the drug tablet may be the same, or the device The drug may change in accordance with the following: The drug may be in other liquid, semi-solid, or solid forms (e.g., granules). ) may also be in forms other than tablets.

[0226] In certain embodiments, the drug delivery device has at least two separate components with a single retaining portion. Contains individual or divided drug portions. Each drug portion is a separate drug portion with a holding portion. It may be a sizing, or the drug portion may be separate within a single drug housing with a holding portion. It can be in that area.

[0227] Each drug portion is separated from the second drug portion by a wall of the drug housing. The division may be defined by parts and at least one divided structure. The divided structure may be, in particular, a syringe A plug that is inserted into a housing such as a dart, ball, or disc, and its size Alternatively, it is fixed in place using adhesive. The segmented structure is then formed, for example, by molding. It may be part of a housing that has been formed in contact with it.

[0228] A device comprising at least two separate parts receives a small amount from the corresponding number of drug reservoirs. It may be suitable for sustained release of at least two drug payloads. The two separate parts are specified herein. As described above, they may have the same or different stereoconfigurations. Two drug payloads The term "code" specifically refers to the content of active ingredients or excipients; salt form or base. Forms such as shape; states such as liquid, semi-solid, or solid; or combinations thereof. They may be the same as each other, or they may be different from each other. Therefore, two distinct The part refers to the two drug payloads being administered simultaneously or at different times, at the same rate or different rates. At a certain rate, via the same release mechanism or different release mechanisms, or any combination thereof. It can be released.

[0229] For example, one drug portion is designed to release its drug payload relatively quickly after implantation. The drug portion may be configured such that it undergoes an induction period before release begins. Or a combination of these. The release initiation of two payloads with different drug portions is The process may be gradual. An example of a rapid-release drug portion is a silicone with a relatively thin wall. A drug portion that acts as a relatively fast-acting osmotic pump, such as a tube, in liquid form or special The drug portion loaded with the drug in a rapidly releasing form such as a separately formulated solid form, relatively immediately Examples include drug moieties with a timing-dependent structure for efficacy degradation, or combinations thereof. Therefore, the device can release the drug during the initial acute phase and the maintenance phase.

[0230] As another example, one drug payload may be proportional to the other drug payloads. It may be configured to be released at a relatively fast rate. For example, one drug portion may be compared after transplantation. For rapidly initiated, diffusible release, the drug payload may be contained in a low-water-soluble form. The drug portion contains a drug payload that is highly water-soluble for osmotic release after the induction period. As another example, one drug portion has an aperture with a fast-acting, degradable timing membrane. It can contain the drug payload in liquid state for rapid release through the squeegee, and another drug portion is Containing a separate drug payload in a solid tablet for delayed release following solubilization in vivo. Yes, it is possible. As yet another example, one drug portion may have a relatively hard wall, while another The drug portion is formed to penetrate the wall, which can increase the rate of release through diffusion. Due to increased permeability of water or drugs through a few apertures or pores, or walls It may have a closed-cell porous wall that can increase the release rate.

[0231] The emission components may be combined to achieve a desired emission profile. For example, The device exhibits different induction or delay times, particularly before the start of the initial emission, after the start of emission. The drug is released at different rates or according to different release curves, or the drug load is substantially Releasing drugs over different periods of time before they are effectively depleted, or a combination of these. It may include a release portion. Different release portions may be from the drug delivery device as a whole. The desired release profile, for example, exhibits a relatively short initial delay time, followed by a long-term delay. It is designed to achieve an emission profile that shows sustained emission at a relatively constant rate. They can be combined.

[0232] By combining multiple different drug components into a single device, the device can be replaced The desired release profile of the anti-antagonist can be shown from the device as a whole. The emission profile may be the sum of the emission profiles of separate parts, for example, The first part shows the minimum delay time before the start, and the second part shows the short induction period during which the osmotic gradient develops. Part 2, and part 3, which shows a long delay before the dissolution or decomposition of the degradable structure begins. It includes part 3. Once the release begins from any one part, the release rate will be relatively high for a long period of time. It may be of the order B, and the decay period continues. The three different parts are examples, and any separate part It should be noted that the number or combination of these may be used to achieve the desired emission profile. It should be done.

[0233] Because the different drug portions are simply separated areas within a single tubular housing, Chairs may be relatively simple, which is advantageous for construction and deployment, and further Different drug portions have different drug payloads, aperture configurations, and degradation timings. The structure exhibits different release profiles. The drug portion, for example, is made of different materials, thickness, or In other embodiments, the walls of the porous cell structure are used, and the housing has varying lengths. It is also possible to use separate drug housings. Therefore, sustained release is possible in various ways. It can be achieved by the formula. gel

[0234] In another embodiment, the coating material is applied to the bladder wall (for example, the urothelial area within the bladder). (to) may be applied in the bladder, and the coating material may be an antimetabolite or other drug, This promotes the adhesion of the coating material to the bladder wall and ensures the sustained release of the drug throughout the treatment period. The coating material includes one or more excipient materials that provide a gel, ointment, Creams, pastes, films, emulsion gels, tablets, polymers, or these It may be a mucosal adhesion preparation such as a combination. As a mucosal adhesion preparation polymer, hydrogel Lu or hydrophilic polymers, polycarbophils (i.e., Carbopol, etc.), chitosan, Polyvinylpyrrolidone (PVP), lectin, polyethylene glycolate polymer, Lulurose or a combination thereof may be mentioned. A preferred cellulose is methylcellulose. cellulose (MC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC) or a combination thereof are examples. The coating material contains a permeability enhancer. That's fine. Non-specific examples of permeability enhancers include dimethyl sulfoxide (DMSO) and carboxymethyl sulfoxide. Sodium hydroxymethylcellulose (NaCMC), lipids, surfactants, or combinations thereof. One example is the coating material, which is designed to adhere to the bladder wall. It may be deployed within the vesicle.

[0235] The coating material is deployed inside the bladder using a deployment device. The deployment device guides the body's natural lumens to reach the intended transplant site. It may be any device designed for this purpose. For deployment within the bladder, The royment device is sized and shaped to pass through the patient's urethra into the bladder. The Royment device is a known device such as a catheter or cystoscope, or a specially designed device. It may be a device that deploys a coating substance into the body. It is used for cleaning, then removed from the body, and all of the coating material is removed from the body. It is implanted. Once implanted, the coating material can release drugs into the body for a long period of time. Equivalent The procedure involves transferring one of the devices or drugs described herein through another natural lumen. It can be used to deploy to other parts of the body. For example, the deployment device is Liquid drugs or drug formulations are delivered to the bladder by passing them through a deployment device via the urethra. It can be used for deployment within the viscera. A device containing an antimetabolite and a second drug.

[0236] In some embodiments, the intravesical (intravesical) devices provided herein are immunomodulatory. Includes drugs. In some of these embodiments, the intravesical (intravesical) drugs provided herein Vice contains immunomodulatory agents and antimetabolites. In some embodiments, immunomodulatory agents The drugs and antimetabolites are delivered at different rates. III. Kit

[0237] This specification provides kits containing antimetabolites and immunomodulatory agents. In some embodiments, the kit includes an intravesical (intravesical) device containing an antimetabolite. In this embodiment, the kit includes an antimetabolite packaged with an immunomodulatory agent. Includes intravesical (intravesical) devices. In some embodiments, the kit includes an antimetabolite and This includes intravesical (intravesical) devices containing immunomodulatory agents. IV. Exemplary Embodiments Embodiment 1. A method for treating urothelial carcinoma of the lower urinary tract in an individual, wherein an effective amount of The procedure includes the step of administering an antagonist to an individual, the antagonist being delivered locally to the bladder. A method. Embodiment 2. A method for enhancing the immune response against urothelial carcinoma of the lower urinary tract in an individual. This includes the step of administering an effective amount of an antimetabolite to the individual, and the antimetabolite is administered to the bladder. A method of localized delivery. Embodiment 3. A method for reducing the recurrence or progression of urothelial carcinoma of the lower urinary tract in an individual, The step includes administering an effective amount of an antimetabolite to the individual, the antimetabolite being administered locally to the bladder. A method of delivery. Embodiment 4. Tumor microscopy for cancer immunotherapy in individuals with urothelial carcinoma of the lower urinary tract A method for improving a small environment, comprising the step of administering an effective amount of an antimetabolite to an individual. The antimetabolite is delivered locally to the bladder. Embodiment 5. A method for sensitizing an individual with urothelial carcinoma of the lower urinary tract for radiotherapy. The procedure includes the step of administering an effective amount of an antimetabolite to an individual, wherein the antimetabolite is used in the bladder. A method of local delivery to the bladder. Embodiment 6. Any of Embodiments 1 to 5, wherein the antimetabolite is a nucleoside analog. The method described in item 1. Embodiment 7. The method according to Embodiment 6, wherein the antimetabolite is gemcitabine. Embodiment 8. The antimetabolite is continuously released into the bladder for at least about 24 hours. A method according to any one of embodiments 1 to 7, which is delivered. Embodiment 9. The antimetabolite is delivered at a first release rate during the first delivery period. Subsequently, a second period of delivery having a second release rate follows, in any of embodiments 1 to 8. Methods used. Embodiment 10. An antimetabolite is delivered in a first dose at a first time of delivery, Subsequently, any of Embodiments 1 to 9 is delivered at a second time of delivery in a second dose. The method described in item 1. Embodiment 11. The first period and the second period are continuous, as in Embodiment 9 or 10. Method of description. Embodiment 12. An embodiment in which the first period and the second period are separated by a drug-free period. The method described in state 9 or 10. Embodiment 13. The antimetabolite is delivered in a dose of approximately 1 mg / day to approximately 300 mg / day. or the method according to any one of Embodiments 1 to 9. Embodiment 14. The concentration of gemcitabine in urine is approximately 0.1 μg / mL to approximately 2 μg / mL during the delivery period. The method according to any one of Embodiments 1 to 13, wherein the concentration is 00 μg / mL. Embodiment 15. The concentration of the antimetabolite in the urine is approximately 1 μg / mL to approximately 10 μg / mL during the delivery period. The method according to Embodiment 14, wherein the concentration is g / mL. Embodiment 16. The concentration of the antimetabolite in the urine is approximately 10 μg / mL during the delivery period. The method according to Embodiment 15. Embodiment 17. An embodiment in which the concentration of antimetabolites in the plasma of an individual is less than approximately 1 μg / ml. The method described in any of Forms 1 to 16. Embodiment 18. During the delivery of antimetabolites, antimetabolites in the individual's urine versus metabolites in plasma The method according to any one of Embodiments 1 to 17, wherein the ratio of antagonists is greater than approximately 500:1. Law. Embodiment 19. The antimetabolites are delivered over a period of at least one month, and each antimetabolite The delivery period is at least 1 day, and the interval between each antimetabolite delivery period is approximately 1 week or less. The method according to any one of embodiments 1 to 18, as shown below. Embodiment 20.a) The concentration of antimetabolites in the urine of the individual is at least about 0.1 μg / mL a) the first antimetabolite delivery period; b) the drug-free period; and c) the antimetabolite in the urine of the individual. Implementation including a second antimetabolite delivery period where the concentration of the substance is higher than approximately 0.1 μg / mL. The method described in any of Forms 1 to 19. Embodiment 21. The concentration of antimetabolite in urine is approximately over at least half of the drug-free period. The method according to Embodiment 20, wherein the concentration is higher than 1 μg / mL. Embodiment 22. An embodiment further comprising the step of administering an effective amount of a second drug to an individual. The method described in any one of items 1 to 21. Embodiment 23. The second drug is delivered at the time when antimetabolite delivery is initiated. The method according to Embodiment 22. Embodiment 24. An embodiment in which the second drug is delivered before the delivery of the antimetabolite is initiated. The method described in condition 22. Embodiment 25. The second drug is delivered after the delivery of the antimetabolite has started. The method described in condition 22. Embodiment 26. An embodiment in which the second drug is delivered after the delivery of the antimetabolite has been completed. The method described in condition 22. Embodiment 27. An embodiment in which the antimetabolite delivery period and the second drug delivery period overlap with each other. The method according to any one of forms 22 to 26. Embodiment 28. An embodiment in which the delivery period of the antimetabolite and the delivery period of the second drug do not overlap. The method described in any one of states 22 to 26. Embodiment 29. Any of Embodiments 22 to 28, wherein the second drug is delivered systemically. The method described in item 1. Embodiment 30. Any of Embodiments 22 to 28, wherein the second drug is delivered locally. The method described in item 1. Embodiment 31. The second drug is delivered systemically during the first period of the second drug delivery period. Embodiment 2 is characterized by the following: local delivery during the second phase of the second drug delivery period. The method described in any one of items 2 to 30. Embodiment 32. The second drug is delivered locally at a first time during the second drug delivery period. Embodiment 2 is characterized by the following: systemic delivery during the second phase of the second drug delivery period. The method described in any one of items 2 to 30. Embodiment 33. The first time of the second drug delivery period and the second time of the second drug delivery period The method according to embodiments 31 and 32, wherein the period is separated for at least about one month. Embodiment 34. An antimetabolite and a second drug are delivered simultaneously, in the same manner as in Embodiment 22. Method of description. Embodiment 35. An antimetabolite and a second drug are delivered via a single delivery device. The method according to embodiment 34. Embodiment 36. An embodiment in which an antimetabolite and a second drug are delivered at the same release rate. The method described in form 35. Embodiment 37. An antimetabolite and a second drug are delivered at different release rates. The method described in form 35. Embodiment 38. Further comprising the step of delivering a second drug separately from an antimetabolite, The method according to any one of embodiments 34 to 37. Embodiment 39. The method according to Embodiment 38, wherein the second drug is delivered systemically. Embodiment 40. The method according to Embodiment 38, wherein the second drug is delivered locally. Embodiment 41. Any one of Embodiments 22 to 40, wherein the second drug is a chemotherapeutic agent. Methods used. Embodiment 42. The second drug is paclitaxel, docetaxel, carboplatin, cis The method according to Embodiment 41, selected from the group consisting of platin and oxaliplatin. . Embodiment 43. Any of Embodiments 22 to 40, wherein the second agent is an immunomodulatory agent. The method described in item 1. Embodiment 44. The immunomodulatory agent is an immune checkpoint inhibitor, in Embodiment 43. Method of description. Embodiment 45. The immune checkpoint inhibitor is PD-L1, CTLA4, PD-L2 PD-1, B7-H3, B7-H4, HVEM, B and T lymphocyte attenuators ( BTLA, killer inhibitor receptor (KIR), GAL9, TIM3, A2AR, LAG-3 Phosphatidylserine, CD27, TNF-α, CD33, Siglec-5, Sig Immunotherapy selected from the group consisting of lec-7, Siglec-9, and Siglec-11. The method according to Embodiment 44, which is an inhibitor of an epidemic checkpoint protein. Embodiment 46. Embodiment 43, in which the immunomodulatory agent is an agonist of a co-stimulatory immune molecule. Methods used. Embodiment 47. The co-stimulatory immune molecules are CD40, OX40, ICOS, CD28, CD1 37 / 4-1BB, CD27, IL-10, TGF-beta, TOR receptor and glucon Selected from the group consisting of corticoid-inducible TNFR-related proteins GITR, The method described in condition 46. Embodiment 48. An individual that does not receive radiation therapy, according to any one of Embodiments 1 to 47. Method of description. Embodiment 49. The embodiment described in any one of Embodiments 1 to 48, further comprising radiotherapy. method. Embodiment 50. An antimetabolite is delivered in a neoadjuvant state, from Embodiment 1 The method described in any one of item 49. Embodiment 51. Embodiments 1 to 49 in which an antimetabolite is delivered in an adjuvant state. The method described in any one of the items. Embodiment 52. Further comprising a third treatment including surgery, wherein delivery of an antimetabolite to an individual, The method according to any one embodiment 1 to 51, which is initiated at the time of surgery. Embodiment 53. An embodiment in which the delivery of an antimetabolite to an individual is initiated during a cystoscopy. The method described in any one of states 1 to 52. Embodiment 54. An antimetabolite is delivered into the bladder by an intravesical delivery device. The method according to any one of Embodiments 1 to 53. Embodiment 55. A housing configured for intravesical insertion of an intravesical device; The housing contains a drug formulation that includes an antimetabolite, and the housing holds the drug formulation, and urothelial carcinoma Embodiment 54 describes a configuration that releases an antimetabolite in an amount effective for the treatment of [the condition]. The method. Embodiment 56. An intravesical drug delivery device comprising an antimetabolite, which is controllable The retaining shape is configured to release and hold the device in the individual's bladder and urethra. Elastically deformable between the deployment shape and the device's passage through it. The method according to any one of embodiments 54 to 55, including wagging. Embodiment 57. The device comprises a drug reservoir lumen with a first wall and a second wall as boundaries. It contains, and the first wall is impermeable to drugs, and the second wall is impermeable to antimetabolites. The method according to embodiment 56, which is permeable. Embodiment 58. The method according to Embodiment 57, wherein the first wall is cylindrical. Embodiment 59. Any one of Embodiments 57 to 58, wherein the second wall is disk-shaped. Methods used. Embodiment 60. The intravesical drug delivery device comprises at least two drug reservoir lumens The method according to any one of embodiments 54 to 59, including the method described in any one of embodiments 54 to 59. Embodiment 61. Embodiment 5, in which an antimetabolite is released from the device by osmosis. The method described in any one of items 4 to 60. Embodiment 62. Embodiment 54, in which an antimetabolite is released from the device by diffusion. The method described in any one of paragraphs 61 to 61. Embodiment 63. Embodiment in which the antimetabolite contained in the housing is in a non-liquid form. The method described in any one of items 54 to 62. Embodiment 64. The non-liquid form is a tablet, granules, semi-solid, capsule, or a combination thereof. The method according to embodiment 63, selected from the group. Embodiment 65. The urothelial carcinoma is bladder cancer, as described in any one of Embodiments 1 to 64. Method of loading. Embodiment 66. The bladder cancer is locally advanced bladder cancer or metastatic bladder cancer. The method according to embodiment 65. Embodiment 67. Any of Embodiments 64 to 65, wherein the bladder cancer is muscle-invasive bladder cancer. The method described in item 1. Embodiment 68. Any of Embodiments 64 to 65, wherein the bladder cancer is non-muscle-invasive bladder cancer. The method described in item 1. Embodiment 69. The bladder cancer is carcinoma in situ, as described in any one of Embodiments 64 to 65. Method of loading. Embodiment 70. Bladder cancer is BCG (Calmette-Guérin bacillus) refractory cancer or papilloma The method according to any one of embodiments 64 to 65, wherein the cancer is bladder cancer. Embodiment 71. The method according to any one of Embodiments 1 to 70, wherein the individual is a human. Embodiment 72. An individual is unsuitable for systemic treatment, one of Embodiments 1 to 71. The method described in section [section number]. Embodiment 73. An individual having an impaired immune system, one of any of Embodiments 1 to 72 The method described in section [section number]. Embodiment 74. An individual having a high level of immune checkpoint protein, The method described in any one of states 1 to 73. Embodiment 75. An individual having low levels of immune checkpoint proteins, The method described in any one of states 1 to 73. Embodiment 76. An individual having a high level of nucleoside transporter, as in Embodiments 1 to 75. The method described in any one of the items. Embodiment 77. An individual having a low level of nucleoside transporter, as in Embodiments 1 to 75. The method described in any one of the items. Embodiment 78. The antimetabolite is gemcitabine, and the method is gemcitabine / metabolism in urine Embodiment 1 further includes a step of determining the ratio, wherein a ratio below a threshold indicates an effective treatment. The method described in any one of paragraphs 77 to 77. Embodiment 79. a) an antimetabolite and b) a second drug comprising the lower urinary tract in an individual. A kit for treating urothelial carcinoma, wherein an antimetabolite is delivered locally to the bladder. A kit containing a device for this purpose. Embodiment 80. The kit according to Embodiment 79, wherein the antimetabolite is gemcitabine. Embodiment 81. The kit according to Embodiment 79 or 80, wherein the second agent is an immunomodulator. to. Embodiment 82. A housing containing an antimetabolite and an immunomodulator is used to deliver a substance to the bladder of an individual. A delivery device for local delivery of an antimetabolite and a second drug, housing The device is designed to provide local release of an antimetabolite and a second drug into the individual's bladder. A delivery device has been created. Embodiment 83. The delivery device according to Embodiment 82, wherein the antimetabolite is gemcitabine. vinegar. Embodiment 84. Delivery according to Embodiment 82 or 83, wherein the second drug is an immunomodulator. device. Embodiment 85. A bladder cavity drug delivery device comprising a housing defining a reservoir; A first unit contained within the bar, the first unit containing an antimetabolite; and A second unit, which is located in the reservoir at a position separate from the first unit, A second unit containing a functional agent that promotes the in vivo release of drugs from the wrigg The method according to any one of embodiments 54 to 56, including the method according to any one of embodiments 54 to 56. Embodiment 86. A method for treating muscle-invasive bladder cancer in an individual, comprising an effective amount of gem The procedure includes the step of delivering gemcitabine locally to the bladder, and gemcitabine remains for at least 24 hours. A method of continuous delivery over a period of time. Embodiment 87. A method for bladder preservation in an individual, comprising administering an effective amount of gemcitabine to the bladder. The step involves local delivery, and gemcitabine is sustained for at least 24 hours. A method of delivery. Embodiment 88. Embodiment 86 in which gemcitabine is delivered by an intravesical device. Or the method described in 87. Embodiment 89. A housing configured for intravesical insertion of an intravesical device; The housing contains a drug formulation that includes an antimetabolite, and the housing holds the drug formulation, and urothelial carcinoma Embodiment 88 describes a configuration that releases an antimetabolite in an amount effective for the treatment of [the condition]. The method. Embodiment 90. An intravesical drug delivery device comprising an antimetabolite, which is controllable The retaining shape is configured to release and hold the device in the individual's bladder and urethra. Elastically deformable between the deployment shape and the device's passage through it. The method according to embodiment 88 or 89, including woozing. Embodiment 91. The intravesical device contains 225 mg of gemcitabine, as in Embodiment 88. The method described in any one of paragraphs 90 to 90. Embodiment 92. Gemcitabine is administered to an individual's bladder for a period of 24 hours to 3 weeks. The method according to any one of embodiments 86 to 91, which is delivered to a target. Embodiment 93. Gemcitabine is continuously delivered to the individual's bladder over a period of 7 days. The method according to any one of embodiments 86 to 92. Embodiment 94. Any of Embodiments 86 to 93, including two gemcitabine delivery periods. The method described in item 1. Embodiment 95. An embodiment in which the first and second gemcitabine delivery periods are each 7 days. The method described in condition 94. Embodiment 96. The first and second gemcitabine delivery periods are separated by a 14-day drug-free period. The method according to embodiment 94 or 95, wherein the separation is performed. Embodiment 97. An individual unsuitable for radical cystectomy, as described in Embodiments 86 to 96. The method described in either of the above terms. Embodiment 98. An individual is subjected to systemic chemotherapy and / or drugs other than antimetabolites. The method according to any one of embodiments 86 to 97, wherein chemotherapy is not permitted. Embodiment 99. Any of Embodiments 86 to 98 in which the individual does not undergo radical cystectomy. The method described in item 1. Embodiment 100. A method for treating non-muscle-invasive bladder cancer in an individual, wherein gemshita The procedure includes the step of locally delivering the vial to the bladder, and gemcitabine is delivered within at least 24 hours. A method of continuous delivery over time. Embodiment 101. Gemcitabine is delivered by an intravesical device, Embodiment 1 Methods for 00. Embodiment 102. An intravesical device comprising a housing configured for intravesical insertion; and a dosage form containing an antimetabolite, the housing holds the dosage form and urothelium Embodiment 101 is configured to release an antimetabolite in an amount effective for treating cancer. Method of description. Embodiment 103. An intravesical drug delivery device comprising an antimetabolite, which is controllable. The retaining shape is configured to release and hold the device in the individual's bladder and the individual's urine Elastically deformable between the deployment shape and the path for the device to pass through. The method according to embodiment 101 or 102, including a housing. Embodiment 104. The intravesical device contains 225 mg of gemcitabine, Embodiment 1 The method described in any of 01 to 103. Embodiment 105. Gemcitabine is retained in the individual's bladder for a period of 24 hours to 3 weeks. The method according to any one of embodiments 100 to 105, which is delivered sequentially. Embodiment 106. Gemcitabine is continuously delivered to the individual's bladder over a period of 7 days. The method according to any one of embodiments 100 to 106. Embodiment 107. Including a first gemcitabine delivery period and a second gemcitabine delivery period The method according to any one of embodiments 100 to 106. Embodiment 108. The first and second gemcitabine delivery periods are each 7 days. The method described in morphology 107. Embodiment 109. The first and second gemcitabine delivery periods are accompanied by a 14-day drug-free period. The method according to embodiment 107 or 108, which is separated as follows. Embodiment 110. The embodiment described in any one of Embodiments 86 to 109, wherein the individual is a human. method. Embodiment 111. Gemcitabine is continuously delivered to the individual's bladder over a period of 7 days. The method according to any one of embodiments 7 to 78. Embodiment 112. Gemcitabine is continuously delivered to the individual's bladder over a period of 3 weeks. The method according to any one of embodiments 7 to 78. Embodiment 113. Embodiments 7 to 78, 111, including two gemcitabine delivery periods. or the method described in any one of paragraphs 112. Embodiment 114. The first and second gemcitabine delivery periods are each 7 days. The method described in morphology 113. Embodiment 115. The first and second gemcitabine delivery periods are each 3 weeks. The method described in morphology 113. Embodiment 114. The first and second gemcitabine delivery periods are separated by a drug-free period. The method according to any one of embodiments 113 to 115. Embodiment 115. The method according to Embodiment 114, wherein the drug-free period is 14 days. Embodiment 116. The method according to Embodiment 114, wherein the drug-free period is 14 days to 12 weeks. . Embodiment 117. Gemcitabine is continuously delivered to the individual's bladder over a period of 3 weeks. or the method according to any one of embodiments 100 to 104. Embodiment 118. The first gemcitabine delivery period and the second gemcitabine delivery period are The method according to Embodiment 107, wherein each period is 3 weeks. [Examples]

[0238] (Example 1) The orthotopic bladder cancer model involves the sustained use of gemcitabine in the bladder after treatment with human bladder cancer cell lines. Developed in rats to enable evaluation of the effectiveness of targeted administration. Thymus-deficient Noodle The rats were treated with a cannula on day 0. On day 3, fluorescently labeled T24 human bladder cancer cells were introduced into the rats. The drug was injected. The tumor was observable on day 5 of the study. Gemcitabine perfusion was started on day 6. It persisted until day 11. Three concentrations of gemcitabine were tested: 90 μg / ml, 18 0 μg / ml and 350 μg / ml. As shown in Figure 1, the gel over a 5-day study period. Continuous administration of cytabine 90 μg / ml resulted in significant reductions in tumor volume compared to untreated controls. It leads to a reduction. The antitumor effect increased with increasing gemcitabine dosage.

[0239] Eleven days later, the bladder was removed and subjected to histological analysis. A strong inflammatory response was observed in all three types of tissue examined. The gemcitabine concentration was observed. The higher the concentration, the wider the area of ​​necrosis and the inflammation. Cellular infiltration was observed at the drug release site.

[0240] In rats treated with gemcitabine, urine and blood parameters were measured. No significant differences were found. Hematuria was observed in all perfused animals. It was done.

[0241] Gemcitabine is acceptable in all perfusion groups, with mild to moderate weight loss. The number of deaths (2 / 6) was lower with high-dose gemcitabine treatment (350 μg / ml). It was observed. (Example 2)

[0242] The miniature pig model uses an intravesical (intravesical) device to locally and continuously treat the bladder. Developed to investigate the effects of administering mucitabine. For this study, Gem Cytabine was continuously administered to miniature pigs for one week using an intravesical (intravesical) device. The intravesical (intravesical) device was removed on day 7. Following the removal of the device, Gemcitabine The concentrations of gemcitabine and its active metabolites were measured in the urine of miniature pigs. Based on metabolite levels, therapeutic gemcitabine levels in bladder tissue were estimated. In particular, the appropriate level of gemcitabine for treatment persists well even after the device is removed. It was done. (Example 3)

[0243] The pilot study conducted involved localized and continuous administration of gemcitabine to the bladder. Ossprag Dolly rats were used to determine the pharmacokinetic and pharmacodynamic properties of the rat. A rat was fitted with an intravesical cannula (IUBC) and radiolabeled. 14 C-gemcitabine Perfuse for 6 or 24 hours at a rate of 300 μL / hour and a gemcitabine concentration of 3.85 mg / mL. The gemcitabine concentration was measured in various tissue layers. Surprisingly, as shown in Figure 3, Gemcitabine can penetrate deep bladder tissue. Radiation labeling is most concentrated in the outer membrane and epithelium. This was followed by the muscle and lamina propria in that order. (Example 4)

[0244] Syngeneic rat models evaluate the efficacy and immunological effects of continuous local administration to the bladder. Developed for the purpose of treating Wistar rats with cannulas on day 0, and NBT-II rats. Bladder tumor cells were injected on day 3. The tumor was allowed to grow for 5 days before perfusion was started on day 8. During days 8-13 of the study, gemcitabine was administered at a concentration of 90 μg / ml or 180 μg / ml. The rats were euthanized on the 14th day. Samples derived from tumors, spleen, blood, and plasma were collected. Textile pathology and immunohistochemistry, flow cytometry and cytokine profiling It was recovered for the purpose of [something].

[0245] The levels of activated CD8+ and CD4+ T cells, as well as CD+4 and CD8+ regulatory cells The levels were measured in the tumor microenvironment compared to the levels shown in Figure 4. The treatment involved the activation of regulatory T cells (CD+4 and CD8+ T cells) in the tumor microenvironment. The ratio to gemcitabine decreased. The levels of activated CD4+ and CD8+ cells were reduced. It was enlarged in the spleen of rats treated with (Figure 5). Without being bound by theory, The effects observed on activated CD4+ and CD8+ cells were related to the bloodstream of bladder tumor antigens. This can result from the transport and clonal expansion of enhanced T cells following the release.

[0246] Plasma TGFβ and IL-10 levels were also measured following gemcitabine delivery. See Figure 6. As shown, TGFβ levels were higher in gemcitabine-treated rats compared to control animals. It decreased in T. It is known that inhibition of TGFβ impairs Treg activation. Figure As shown in 7, IL-10 levels increased with gemcitabine delivery.

[0247] These results demonstrate that sustained and localized delivery of gemcitabine elicits an immune response. They are doing it. (Example 5)

[0248] In the ongoing Phase 1b study, TAR-200-101 is being treated with a curative lymph node dissection. A confirmed muscular invasive bladder is being planned for radical cystectomy (RC). In patients with epithelial carcinoma (clinical and pathological stage pT2a), over a 28-day period 225 patients were divided into groups using the GemRIS system with a 14-day drug-free period. The safety of gemcitabine administered intravesically in mg over 7 days for up to two dose cycles. Designed to evaluate acceptance.

[0249] Gemcitabine Releasing Intravesical Syst em(GemRIS) was placed in the bladder via an inserter on day 0 of the study, and on day 7 of the study... Remove. GemRIS gradually releases gemcitabine over a 7-day period of indwelling. Second GemRIS was placed in the bladder on day 21 of the study and removed on day 28, the day of the TURBT. GemRIS's main mode of action is the sustained release of gemcitabine into the bladder over a 7-day period. It is a passive, non-absorbable gemcitabine-releasing intravesical (intravesical) system.

[0250] Arm 1 has residual tumor after TURBT. TAR-200 (GemRIS) is used. The TAR-200 is placed in the bladder on day 0 of the study via an inserter and removed on day 7 of the study. Gemcitabine is gradually released during the 7-day indwelling period. The second TAR-200 was studied in 21 The device is placed in the bladder on day 1 and removed on day 28 of the study, which is the day of radical cystectomy (RC).

[0251] Arm 2 has no residual tumor after TURBT. TAR-200 (GemRIS) The TAR-200 is placed in the bladder on day 0 of the study via an inserter and removed on day 7 of the study. Gemcitabine is gradually released during the 7-day indwelling period. The second TAR-200 was studied in 21 The device is placed in the bladder on day 1 and removed on day 28 of the study, which is the day of radical cystectomy (RC).

[0252] The patient has histological evidence of muscle-invasive transitional cell carcinoma (stage II-IIIb) of the bladder. It presents with signs of metastatic nodular disease affecting only the obuturator muscles or presacral lymph nodes. Patients who undergo this procedure may be included. Patients who have visible residual urinary tract measured at 3 cm or more after TURBT. Patients must have a localized tumor. Patients included in the study will receive cisplatin-based chemotherapy. Alternatively, they may be deemed ineligible or refuse cisplatin-based chemotherapy. Preceding radiation therapy is permissible, provided that the radiation therapy was not administered to the bladder. In a study on the removal of the investigational product and radical cystectomy after treatment, the bladder You must be eligible to undergo a endoscopic examination and be willing to do so.

[0253] The primary endpoints were encoded using MedDRA and weighted using CTCAE v4.0. The number of participants who experienced adverse events (TEAEs) as a result of treatments categorized by severity. Yes. Secondary endpoints include acceptance of GemRIS implantation on days 1-7 and 21-28. This is the number and percentage of participants. Plasma and urine levels of dFdC and dFdU were also measured. Determine. Secondary effectiveness measures also include:

[0254] 1. Number of participants who tolerate TAR-200 implantation [Period: Day 0 to Day 7]

[0255] 2. Percentage of participants who tolerated TAR-200 implantation [Period: Day 0 to Day 7] ]

[0256] 3. Number of participants who tolerate TAR-200 implantation [Period: from day 21 to day 28] ]

[0257] 4. Percentage of participants who tolerated TAR-200 implantation [Period: Day 21 to Day 28] to]

[0258] 5. Cmax, plasma dFdU. Difluorodeoxyuridine (diflourodeoxyu) in plasma. Analysis of Cmax (maximum concentration reached over time) of ridine (dFdU). [Period: Day 0] [From day 28]

[0259] 6. Tmax, plasma dFdU. Tmax of difluorodeoxyuridine (dFdU) in plasma. Analysis of the maximum concentration (the day the maximum concentration was reached). [Period: Day 0 to Day 28]

[0260] 7. Cavg, plasma dFdU. Concentration of difluorodeoxyuridine (dFdU) in plasma. Descriptive statistics of degree (e.g., sample size, mean and median, quartiles, minimum and maximum) Analysis of box plots. [Period: Day 0 to Day 28]

[0261] 8. Cmax, plasma dFdC. Gemcitabine (deoxydifluorocytidine salt) in plasma. Analysis of Cmax (maximum concentration reached over time) of salt (dFdC). [Period: Day 0 to Day 2] [Up to day 8]

[0262] 9. Tmax, plasma dFdC. Gemcitabine (deoxydifluorocytidine salt) in plasma. Analysis of Tmax (day of reaching maximum concentration) of salt (dFdC) [Period: Day 0 to Day 28] Up to the eyes]

[0263] 10. Cavg, plasma dFdC. Gemcitabine (deoxydifluorocytidine) in plasma. Descriptive statistics (e.g., sample size, mean and median, quartiles) of the concentration of hydrochloride (dFdC) Analysis of values, minimum and maximum values, and box plots [Period: Day 0 to Day 28] to].

[0264] 11. Cmax, urinary dFdU (arm 1 only). Difluorodeoxyuridine in urine ( Analysis of Cmax (maximum concentration reached over time) of dFdU. [Period: Day 0 to Day 28] Up to the eyes]

[0265] 12. Tmax, urinary dFdU (arm 1 only). Difluorodeoxyuridine in urine ( Analysis of Cmax (maximum concentration reached over time) of dFdU. [Period: Day 0 to Day 28] Up to the eyes]

[0266] 13. Tmax, urinary dFdU (arm 1 only). Difluorodeoxyuridine in urine ( Analysis of Cmax (maximum concentration reached over time) of dFdU. [Period: Day 0 to Day 28] Up to the eyes]

[0267] 14. Cavg, urinary dFdU (arm 1 only). Difluorodeoxyuridine in urine ( Descriptive statistics of the concentration of dFdU (e.g., sample size, mean and median, quartiles, minimum) Analysis of values, maximum values, and box plots. [Period: Day 0 to Day 28]

[0268] 15. Cmax, urinary dFdC (arm 1 only). Gemcitabine (deoxydiflu) in urine. Analysis of Cmax (maximum concentration reached over time) of orocitidine hydrochloride (dFdC) [period] [From day 0 to day 28]

[0269] 16. Tmax, urinary dFdC (arm 1 only). Gemcitabine (deoxydiflu) in urine. Analysis of Tmax (day of reaching maximum concentration) of orocitidine hydrochloride (dFdC) [Period: 0 [From day 1 to day 28].

[0270] 17. Cavg, urinary dFdC (arm 1 only). Gemcitabine (deoxydiflu) in urine. Descriptive statistics (e.g., sample size, mean and intermediate) of the concentration of orocitidine hydrochloride (dFdC). Analysis of median, quartile, minimum and maximum values, as well as box plots. [Period: 0 days] [From the eye to day 28]

[0271] 18. Immunohistochemical biomarkers (AKT) for drug-induced cell death in tumor materials Preliminary antitumor effect evaluated (after treatment) (arm 1) [Period: Antitumor analysis was conducted on 28 [This will be performed on the first day of the research visit.]

[0272] 19. Immunohistochemical biomarker (CD31) of drug-induced cell death in tumor tissue Preliminary antitumor effect (arm 1) evaluated at the time of treatment. [Period: Antitumor analysis is This will be performed on the 28th day of the study visit.

[0273] 20. Immunohistochemical biomarker (Ki67) of drug-induced cell death in tumor tissue Preliminary antitumor effect evaluated in the treatment (after procedure) (arm 1) [Period: Antitumor analysis was conducted in 2 This will be performed on the 8th day of the study visit.

[0274] 21. Immunohistochemical biomarkers (TUNEL) for drug-induced cell death in tumors Preliminary antitumor effect evaluated in the material (post-treatment) (arm 1) [Period: Antitumor analysis is This will be performed on the 28th day of the study visit.

[0275] 22. Immunohistochemical analysis of drug-induced cell death and histochemical biomarkers (CD4) in tumor materials. Preliminary antitumor effect evaluated (after treatment) (arm 1) [Period: Antitumor analysis was conducted on 28 [This will be performed on the first day of the research visit.]

[0276] 23. Immunohistochemical analysis of drug-induced cell death and its histochemical biomarker (CD8) in tumor materials. Preliminary antitumor effect evaluated (after treatment) (arm 1) [Period: Antitumor analysis was conducted on 28 [This will be performed on the first day of the research visit.]

[0277] 24. Immunohistochemical biomarker (PD-L1) of drug-induced cell death in tumors Preliminary antitumor effect evaluated in the material (post-treatment) (arm 1) [Period: Antitumor analysis is This will be performed on the 28th day of the study visit.

[0278] 25. Immunohistochemical biomarkers (AKT) for drug-induced cell death in tumor materials Preliminary antitumor effect evaluated (after treatment) (arm 2) [Period: Antitumor analysis was conducted for 42 days] [This will be performed on the first day of the research visit.]

[0279] 26. Immunohistochemical biomarker (CD31) of drug-induced cell death in tumor tissue Preliminary antitumor effect evaluated in the treatment (after procedure) (arm 2) [Period: Antitumor analysis was 4 This will be performed during the follow-up visit on the second day of the study.

[0280] 27. Immunohistochemical biomarker (Ki67) of drug-induced cell death in tumor tissue Preliminary antitumor effect evaluated in the treatment (after procedure) (arm 2) [Period: Antitumor analysis was 4 This will be performed during the follow-up visit on the second day of the study.

[0281] 28. Immunohistochemical biomarkers (TUNEL) for drug-induced cell death in tumors Preliminary antitumor effect evaluated in the material (post-treatment) (arm 2) [Period: Antitumor analysis is This will be performed on the 42nd day of the study visit. 29. Immunohistochemistry of drug-induced cell death and histobiomarkers - Preliminary antitumor effect evaluated in tumor material (post-treatment) for (CD4) (arm 2) [Period: Antitumor analysis will be performed on the research day visit, day 42.]

[0282] 29. Immunohistochemical analysis of drug-induced cell death and its histochemical biomarker (CD8) in tumor materials. Preliminary antitumor effect evaluated (after treatment) (arm 2) [Period: Antitumor analysis was conducted for 42 days] [This will be performed on the first day of the research visit.]

[0283] 30. Immunohistochemical biomarker (PD-L1) of drug-induced cell death in tumors Preliminary antitumor effect evaluated in the material (post-treatment) (arm 2) [Period: Antitumor analysis is This will be performed on the 42nd day of the study visit.

[0284] The following eligibility criteria are used: Minimum age 18 years. Histology of muscle-invasive transitional cell carcinoma of the bladder. Proof of disease (Stage II-III). Metastatic nodular disease affecting only the obturator muscles or presacral lymph nodes. Patients exhibiting signs of the condition may be included (N1 M0). Any degree of pelvic lateral wall fixation is acceptable. Subjects with visible residual tumors after TURBT are ineligible. In Arm 1, subjects with visible residual tumors after TURBT are ineligible. This must be done. In Arm 2, a re-stage classification T is performed 2-6 weeks prior to day 0 of the study. The target must be completely resected after URBT (i.e., the visible tumor must be removed). (None or as small as possible tumors). The following requirements must be met within 21 days prior to administration of the medication. Appropriate bone marrow, liver, and kidney function as assessed: a. Hemoglobin ≥ 9.0 g / dL b c. Neutrophil absolute count (ANC) ≥ 1,500 / mm³ c. Platelet count ≥ 100,000 / mm³ 3 d. Total bilirubin ≤ 1.5 × ULN (Upper limit of normal) e. Alanine aminotransfer Aspartate aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ×ULN f. Glomerular filtration rate (GFR) ≥ 30% (≥ 30 ml / min / 1.73 m2). The elephant must be willing to undergo cystoscopy for research purposes to remove any experimental products. The person is eligible and willing to undergo RC (Rapid Consultation) by their assigned urologist. If a medical oncologist deems a patient ineligible for cisplatin-based combination chemotherapy It must be medically appropriate to use neoadjuvant cisplatin-based combination chemotherapy. This refers to individuals who are in a position to refuse this treatment option and who understand the risks and benefits of doing so. Preceding radiation therapy is acceptable, provided that the radiation therapy was not administered to the bladder. Consent form for disclosure of personal medical information and the 1966 health insurance interoperability and accountability Approval under the Act on Personnel Management (HIPAA). Age > 18 at the time of consent.

[0285] Use the following elimination criteria: The patient is treated with the expectation of a curative outcome and there is no risk of metastasis or death. Active malignant tumors within the last 12 months, excluding those with negligible risk. Transitional cell carcinoma of the bladder. Prior systemic chemotherapy. Any other prior systemic chemotherapy for non-urothelial carcinoma. This must also be completed more than 5 years before the start of the research. Preceding exposure to gemcitabine administration Dew. Other intravesical chemotherapy currently being received. Concurrent clinically determined by the treatment investigator. Important infection. In the investigator's opinion, safe placement, retention, or removal of the TAR-200 is not possible. The presence of any anatomical features of the bladder or urethra that may obstruct the condition. A confirmed history of vesicoureteral reflux. Alternatively, the presence of an indwelling ureteral stent or nephrostomy tube at the time of screening. 6 months prior to registration. Pelvic radiation therapy administered within the last month. Eligible individuals are those who received radiation therapy more than six months prior to registration. The patient must not show signs on cystoscopy or symptoms of radiation cystitis. (More than 250 mL) Post-void residual volume (PVR) of the bladder. This includes urinary tract infections that, in the investigator's opinion, are contraindications to participation. Uncontrolled, active, uncontrolled genitourinary bacterial, viral, or fungal infections. Skin / nail fungal infections are Subjects with active herpes zoster (varicella-zoster infection) are excluded from the study. In the investigator's view, any severe cardiovascular, lung, liver, kidney, or stomach condition is a contraindication to participation. Intestinal, gynecological, endocrine, immunological, dermatological, neurological or psychiatric disorders or History or presence of a disorder. History of diagnosis of neurogenic bladder. Steroids at a dose of 5 mg or less per day. Excluding concomitant immunosuppressants such as methotrexate or TNF inhibitors within two weeks of day 0 of the study. Antipharmacological drug therapy. Difficulty in providing blood samples. Planned visits and follow-up. Any condition (physical, mental, or social) that may affect the recurrence of the subject By agreeing to informed consent, including the existence of such consent, or by complying with the requirements of this protocol... Not wanting to or being unable to do something. In the view of the researcher or TARIS, Any other unspecified reasons why the elephant is unsuitable for registration.

[0286] The medication was administered to 10 subjects. There were no significant adverse events or discontinuations related to the treatment, and GemR There was also no target for IS removal. Cystitis or gross hematuria was not reported. Fur thermore, there were no signs of anemia, neutrophilia or thrombocytopenia typically seen with IV or systemic administration of gemcitabine, and no events that caused delays in RC. There was also no chemical cystitis. Preliminary pharmacokinetic analysis for 10 subjects was completed, demonstrating measurable urinary levels of gemcitabine and dFdU (intracellular metabolite). The plasma concentration of gemcitabine was below the quantitative assay limit (0.1 mcg / mL) in all plasma samples analyzed (n = 55). Low but quantifiable plasma concentrations of dFdU in the range of 0.104 - 0.284 mcg / mL were observed in 10 out of 55 plasma samples analyzed.

[0287] All enrolled subjects had a remaining size measured at 3 cm or more, consistent with large muscle-invasive disease, and had a visible, exophytic, papillary tumor. Notably, 5 out of these 10 treated subjects had no visible tumor at the time of RC, suggesting treatment efficacy during the 28-day dosing period. Of the remaining 5 subjects with visible tumors at RC, 3 showed a significant reduction in the volume of the exophytic tumor, and the remaining 2 (each with a pT3 stage disease) had persistent disease. 4 out of 10 subjects had no histological signs of residual muscle-invasive disease (<pT2) at the time of cystectomy, including 1 subject with a complete pathological response. Unexpectedly, 9 out of 10 subjects had no incidence in any lymph nodes at the time of RC. The incidence rate in the history of lymph node involvement is 20 - 40%. Furthermore, through RC, no clinical stage (cT2, cT3) was diagnosed in any subject.​​​​​​​​​ None of the patients were classified into a higher pathological stage at the final pathological stage. 42% of patients with medically staged MIBC subsequently had a final pathological diagnosis. This is surprising considering it falls into a higher stage in the stage classification system. Furthermore, recent studies suggest that a pathological staging system at the RC stage leads to a better prognosis. This suggests that preliminary pathological efficacy results to date are summarized in Table 1. The preliminary antitumor effect is due to the immunohistochemical biomarker (CD) of drug-induced cell death. 4. Evaluation of tumors (CD8, PD-L1, AKT, CD31, Ki67, TUNEL) It can be evaluated in the ulcer material (after treatment).

[0288] Several patients treated with GemRIS had inflammation around the tumor, but were involved The surrounding urothelium, where the tumor was absent, appeared normal, showing a remarkable antitumor effect. This is because immunotherapy was used. This is consistent with macroscopic findings observed after the procedure.

[0289] In addition to the remarkably harmless and safe profile observed to date, GemRIS is a cyst In the population eligible for resection, significant and predictable results can be obtained using the currently permitted 28-day window procedure. It has demonstrated preliminary clinical efficacy outside of the field. GemRIS allows for even longer-term treatment. It may offer a substantially higher benefit to some patients who are unsuitable for cystectomy. [Table 1] (Example 5)

[0290] The ongoing Phase 1b study, TAR-200-102, is investigating the diagnosis and transurethral involvement of bladder tumors. Low or moderate recurrence of non-muscle-invasive bladder cancer (NMIBC) between transurethral resection (TURBT) and transurethral resection (TURBT). In patients with a moderate risk, using the GemRIS system over a 28-day period. The 225 mg dose was divided into 14-day drug-free periods and administered intravesically over 7 days. This study is designed to evaluate the safety and tolerability of gemcitabine up to two dose cycles.

[0291] Gemcitabine Releasing Intravesical Syst em(GemRIS) was placed in the bladder via an inserter on day 0 of the study, and on day 7 of the study... Remove. GemRIS gradually releases gemcitabine over a 7-day period of indwelling. Second GemRIS was placed in the bladder on day 21 of the study and removed on day 28, the day of the TURBT. GemRIS's main mode of action is the sustained release of gemcitabine into the bladder over a 7-day period. It is a passive, non-absorbable gemcitabine-releasing intravesical (intravesical) system.

[0292] Arm 1: Experiment: 7-day regimen TAR-200 (GemRIS), inserter Throughout the study, the TAR-200 was placed in the bladder on day 0 and removed on day 7. During the retention period, gemcitabine is gradually released. A second TAR-200 is administered to the bladder on day 21 of the study. Place the sample in place and remove it on day 28 of the study, which is the day of the TURBT. Drug: Gemcitabine- Releasing Intravesical System(GemRIS / TAR TAR-200 is primarily used to stimulate the bladder with gems over the duration of its placement. This is a passive, non-absorbable gemcitabine-releasing intravesical system that provides sustained release of Tabin.

[0293] Arm 2: Experiment: 21-day regimen TAR-200, research day 0 via inserter The device is placed in the bladder and removed on day 21 of the study. The TAR-200 is used during the 21-day indwelling period. Gradually release mucitabine. Place a second TAR-200 in the bladder on day 21 of the study. Remove on day 42. Drug: Gemcitabine-Releasing Intra Vesical System (GemRIS) / TAR-200. The TAR-200 is, Its primary mode of action is the sustained release of gemcitabine into the bladder over the duration of its placement, passive, non- This is an absorbable gemcitabine-releasing intravesical system.

[0294] The patients included in the study underwent in situ (pTis) pathological stage pT1 (mucosal solidification). It was determined that it was not a carcinoma with invasiveness into the lamina and not infiltrating the muscle (pT2). Histologically confirmed bladder urine, excluding highly malignant diseases that are resectable (or exceeding that level) The patient has a history of low or moderate risk of urothelial carcinoma.

[0295] The primary endpoint was encoded using MedDRA, and severity was assessed using CTCAE v4.0. This is the number of participants who experienced adverse events (TEAEs) as a result of treatments categorized by degree. [Duration: 59 days from the time the informed consent form was signed until the last study visit] Until. ]. Secondary endpoints include acceptance of GemRIS placement on days 1-7 and 21-28. The number and percentage of participants by sex. Plasma and urine levels of dFdC and dFdU. It also measures.

[0296] Preliminary antitumor effects include immunohistochemical histomarkers of drug-induced cell death (AKT). The tumor material (post-treatment) was evaluated for the purpose of assessing CD31, Ki67, and TUNEL. The secondary outcome measures include:

[0297] 1. Number of participants (arm 1) who are tolerant to TAR-200 implantation. [Period: from day 0] [Up to day 7]

[0298] 2. Percentage of participants who tolerated TAR-200 implantation (Arm 1). [Period: Day 0] [From day 7]

[0299] 3. Number of participants who tolerate TAR-200 implantation (arm 1). [Period: Day 21] [Up to day 28]

[0300] 4. Percentage of participants who tolerated TAR-200 implantation (Arm 1). [Duration: 21 days] [From the eye to day 28]

[0301] 5. Cmax, plasma dFdU (arm 1). Difluorodeoxyuridine (d Analysis of Cmax (maximum concentration reached over time) of FdU. [Period: Day 0 to Day 32] to]

[0302] 6. Tmax, plasma dFdU (arm 1). Difluorodeoxyuridine (d Analysis of Tmax (day when maximum concentration was reached) of FdU. [Period: Day 0 to Day 32] ]

[0303] 7. Cavg, plasma dFdU (arm 1). Difluorodeoxyuridine (d) in plasma. Descriptive statistics of FdU concentration (e.g., sample size, mean and median, quartiles, minimum) Analysis of the maximum value and box plot. [Period: Day 0 to Day 32]

[0304] 8. Cmax, plasma dFdC (arm 1). Gemcitabine (deoxydifluo) in plasma. Analysis of Cmax (maximum concentration reached over time) of rositidine hydrochloride (dFdC). [Period] [From day 0 to day 32]

[0305] 9. Tmax, plasma dFdC (arm 1). Gemcitabine (deoxydifluo) in plasma. Analysis of Tmax (day of reaching maximum concentration) of rositidine hydrochloride (dFdC) [Period: 0 days] [From the eye to day 32]

[0306] 10. Cavg, plasma dFdC (arm 1). Gemcitabine (deoxydiflu) in plasma. Descriptive statistics (e.g., sample size, mean and intermediate) of the concentration of orocitidine hydrochloride (dFdC). Analysis of median, quartile, minimum and maximum values, as well as box plots. [Period: 0 days] [From the eye to day 32]

[0307] 11. Cmax, urinary dFdU (arm 1). Difluorodeoxyuridine (dF) in urine. Analysis of Cmax (maximum concentration reached over time) of dU. [Period: from day 0 to day 32] in]

[0308] 12. Tmax, urinary dFdU (arm 1), difluorodeoxyuridine (dF Analysis of Tmax (day when maximum concentration was reached) for dU [Period: Day 0 to Day 32]

[0309] 13. Cavg, urinary dFdU (arm 1). Difluorodeoxyuridine (dF) in urine. Descriptive statistics of concentration (dU) (e.g., sample size, mean and median, quartiles, minimum) Analysis of the maximum value and box plot. [Period: Day 0 to Day 32]

[0310] 14. Cmax, urinary dFdC (arm 1). Gemcitabine (deoxydifluoro) in urine. Analysis of Cmax (maximum concentration reached over time) of cytidine hydrochloride (dFdC). [Period: [From day 0 to day 32]

[0311] 15. Tmax, urinary dFdC (arm 1). Gemcitabine (deoxydifluoro) in urine. Analysis of Tmax (day of reaching maximum concentration) of cytidine hydrochloride (dFdC). [Period: 0 days] [From the eye to day 32]

[0312] 16. Cavg, urinary dFdC (arm 1). Gemcitabine (deoxydifluoro) in urine. Descriptive statistics (e.g., sample size, mean, and median) of the concentration of cytidine hydrochloride (dFdC) Analysis of quartiles, minimum and maximum values, and box plots [Period: from day 0] [Up to day 32]

[0313] 17. Preliminary antitumor effects are observed in immunohistochemical histochemical biomarkers of drug-induced cell death (A Evaluation of KT, CD31, Ki67, and TUNEL in tumor specimens (post-treatment) It will be valued. (Arm 1) [Period: Antitumor analysis will be performed on day 28, which is the next study visit.]

[0314] 18. Number of participants who are tolerant to TAR-200 implantation (arm 2) [Period: from day 0] [Up to day 21]

[0315] 19. Percentage of participants who tolerated TAR-200 implantation (Arm 2) [Period: Day 0] [From day 21]

[0316] 20. Number of participants who tolerate TAR-200 implantation (arm 2) [Period: Day 21] [Up to day 42]

[0317] 21. Percentage of participants who tolerated TAR-200 implantation (Arm 2) [Period: 21 days] [From the eye to day 42]

[0318] 22. Cmax, plasma dFdU (arm 2). Difluorodeoxyuridine in plasma ( Analysis of Cmax (maximum concentration reached over time) of dFdU. [Period: Day 0 to Day 47] Up to the eyes]

[0319] 23. Tmax, plasma dFdU (arm 2). Difluorodeoxyuridine in plasma ( Analysis of Tmax (day when maximum concentration was reached) of dFdU. [Period: from day 0 to day 47] in]

[0320] 24. Cavg, plasma dFdU (arm 2). Difluorodeoxyuridine in plasma ( Descriptive statistics of the concentration of dFdU (e.g., sample size, mean and median, quartiles, minimum) Analysis of values, maximum values, and box plots. [Period: Day 0 to Day 47]

[0321] 25. Cmax, plasma dFdC (arm 2). Gemcitabine (deoxydiflu) in plasma. Analysis of Cmax (maximum concentration reached over time) of orocitidine hydrochloride (dFdC). [Duration: From day 0 to day 47]

[0322] 26. Tmax, plasma dFdC (arm 2). Gemcitabine (deoxydiflu) in plasma. Analysis of Tmax (day of reaching maximum concentration) of orocitidine hydrochloride (dFdC) [Period: 0 [From day 1 to day 47]

[0323] 27. Cavg, plasma dFdC (arm 2). Gemcitabine (deoxydiflu) in plasma. Descriptive statistics (e.g., sample size, mean and intermediate) of the concentration of orocitidine hydrochloride (dFdC). Analysis of median, quartile, minimum and maximum values, and box plots.

[0324] 28. Cmax, urinary dFdU (arm 2). Difluorodeoxyuridine (dF) in urine. Analysis of Cmax (maximum concentration reached over time) of dU. [Period: from day 0 to day 47] in]

[0325] 29. Tmax, urinary dFdU (arm 2). Difluorodeoxyuridine (dF) in urine. Analysis of Tmax (day when maximum concentration was reached) for dU [Period: Day 0 to Day 47]

[0326] 30. Cavg, urinary dFdU (arm 2). Difluorodeoxyuridine (dF) in urine. Descriptive statistics of concentration (dU) (e.g., sample size, mean and median, quartiles, minimum) Analysis of the maximum value and box plot. [Period: Day 0 to Day 47]

[0327] 31. Cmax, urinary dFdC (arm 2). Gemcitabine (deoxydifluoro) in urine. Analysis of Cmax (maximum concentration reached over time) of cytidine hydrochloride (dFdC). [Period: [From day 0 to day 47]

[0328] 32. Tmax, urinary dFdC (arm 2). Gemcitabine (deoxydifluoro) in urine. Analysis of Tmax (day of reaching maximum concentration) of cytidine hydrochloride (dFdC). [Period: 0 days] [From the eye to day 47]

[0329] 33. Cavg, urinary dFdC (arm 2). Gemcitabine (deoxydifluoro) in urine. Descriptive statistics (e.g., sample size, mean, and median) of the concentration of cytidine hydrochloride (dFdC) Analysis of quartiles, minimum and maximum values, and box plots [Period: from day 0] [Up to day 47]

[0330] 34. Preliminary antitumor effects are observed in immunohistochemical histochemical biomarkers of drug-induced cell death (A Evaluation of KT, CD31, Ki67, and TUNEL in tumor specimens (post-treatment) It will be valued. (Arm 2) [Period: Antitumor analysis will be performed on day 42, which is the next study visit.]

[0331] Inclusion criteria: in situ (pTis), pathological stage pT1 (lamina propria mucosa) Carcinomas that are not infiltrating (pT2 or so) and carcinomas that are not infiltrating (pT2 or so) Excluding highly malignant diseases that are resectable (exceeding this level), histologically confirmed urothelium of the bladder A medical history indicating a low or moderate risk of cancer. Appropriate laboratory parameters. Indications of bladder cancer. A urinalysis screening that does not show clinically significant abnormalities, excluding those that may be related. The patient has not received any aggressive treatment for the simultaneous neoplasm in the past three months, and the treatment has not been effective in completely eliminating the disease. Recovery is required. Patients receiving concurrent hormone therapy for prostate cancer are registered. It is permitted.

[0332] Exclusion criteria: Intravesical BCG therapy and / or exposure to any other. Single postoperative drip. Chemotherapy agents used less than one year prior to registration, excluding those for which no visible tumors were present at the time of screening. And. Any prior exposure to intravesical gemcitabine infusion within the past 12 months. Any bladder or other object that could interfere with the safe placement, retention, or removal of the TAR-200 in the solution This is the presence of anatomical features of the urethra (i.e., bladder diverticulum, complete incontinence). Recurrence is associated with high-grade urinary tract cancer. Patients with a cystic diagnosis. Currently receiving other systemic or intravesical chemotherapy. Within the 6 months prior to registration. Pelvic radiation therapy administered within the following period. Patients who received radiation therapy more than 6 months prior to registration had bladder problems. No signs of radiation cystitis should be present on stoscopy. Post-void residual volume (PVR). Active, uncontrolled urogenital bacterial infections, including urinary tract infections. Illusory or fungal infection. Skin / nail fungal infections are not ruled out. Active herpes zoster (varicella). Subjects with herpes zoster infection will be excluded from the study. Participation will be contraindicated in the investigator's opinion. Any major cardiovascular, pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine, immunological, or dermatological issues. History or presence of medical, neurological, or psychiatric disorders or conditions. Dosage of 5 mg or less per day. Except for the amount of steroids, methotrexate or TNF inhibitors within 2 weeks of day 0 of the study. Combination immunosuppressive drug therapy such as: Pregnant (as determined by urine test at the time of screening) (Confirmed) or breastfeeding, or fertile and using an acceptable method of contraception This applies to women who have not undergone the procedure. It may affect the return of patients for scheduled appointments and follow-up examinations. Informed consent including the presence of any state (physical, mental, or social) You do not agree to or wish to comply with the requirements of this protocol. The fact that, in the opinion of the investigator or TARIS, there is no other indication that the patient is unsuitable for registration. Reasons why it hasn't been done. [Table 2]

Claims

1. A method for treating urothelial carcinoma of the lower urinary tract in an individual, comprising an effective amount of an antimetabolite. The step includes administering the antimetabolite to the individual, wherein the antimetabolite is delivered locally to the bladder, and below The urothelial carcinoma of the urinary tract is a muscle-invasive bladder cancer, according to the method.

2. The method according to claim 1, wherein the individual is unsuitable for radical cystectomy.

3. The said individual undergoes systemic chemotherapy and / or chemotherapy with agents other than the said antimetabolite. The method according to claim 1 or 2, which is not legally permissible.

4. The individual described in any one of claims 1 to 3 does not undergo radical cystectomy. Law.

5. A method for treating urothelial carcinoma of the lower urinary tract in an individual, comprising an effective amount of an antimetabolite. The step includes administering the antimetabolite to the individual, wherein the antimetabolite is delivered locally to the bladder, and below The urothelial carcinoma of the urinary tract is a non-muscle-invasive bladder cancer, according to the method.

6. A method for treating urothelial carcinoma of the lower urinary tract in an individual, comprising an effective amount of an antimetabolite. The step includes administering the antimetabolite to the individual, wherein the antimetabolite is delivered locally to the bladder, The method further comprises the step of administering an effective amount of a second drug to the individual.

7. The antimetabolite is a nucleoside analog, according to any one of claims 1 to 6. method.

8. The method according to any one of claims 1 to 7, wherein the antimetabolite is gemcitabine. 。

9. The gemcitabine is continuously delivered to the individual's bladder over a period of 24 hours to 6 weeks. The method according to claim 8.

10. A method for bladder preservation in an individual, comprising locally delivering an effective amount of gemcitabine to the bladder. The procedure includes the step of administering gemcitabine to the individual's bladder for 24 hours to 6 weeks. A method to deliver a sample to an individual having urothelial carcinoma of the lower urinary tract.

11. The gemcitabine is continuously delivered to the individual's bladder over a period of 24 hours to 3 weeks. The method according to any one of claims 8 to 10, which is achieved.

12. The gemcitabine is continuously delivered to the individual's bladder over a period of seven days, according to the claim. The method described in any one of items 8 to 11.

13. The gemcitabine is continuously delivered to the individual's bladder over a period of three weeks, according to the claim. The method described in any one of items 8 to 11.

14. Claims from 8, comprising a first gemcitabine delivery period and a second gemcitabine delivery period. The method described in any one of the 13 items.

15. The first and second gemcitabine delivery periods are each 7 days, according to claim 14. The method.

16. The first and second gemcitabine delivery periods are each three weeks, as described in claim 14. The method.

17. The first and second gemcitabine delivery periods are separated by a 14-day drug-free period. The method according to any one of claims 14 to 16.

18. The antimetabolite is delivered at a first release rate during the first stage of delivery, The second period of delivery having a second release rate is followed, any one of claims 1 to 17. Methods used.

19. Claim 1, the antimetabolite is delivered in a dose of approximately 1 mg / day to approximately 300 mg / day. The method described in any of 18.

20. The concentration of antimetabolites in urine ranges from approximately 0.1 μg / mL to approximately 200 μg / mL during the delivery period. The method according to any one of claims 1 to 19.

21. The concentration of antimetabolites in urine is approximately 1 μg / mL to approximately 10 μg / mL during the delivery period. The method according to claim 20.

22. Claim 20 states that the concentration of the antimetabolite in the urine is approximately 10 μg / mL during the delivery period. Method of loading.

23. Claims 1 to 2, wherein the concentration of antimetabolites in the plasma of the individual is less than approximately 1 μg / ml. The method described in either of the two methods.

24. During the delivery of antimetabolites, the antimetabolites in the urine of the individual versus the antimetabolites in the plasma The method according to any one of claims 1 to 23, wherein the ratio is greater than approximately 500:

1.

25. a) The concentration of an antimetabolite in the urine of the individual is at least about 0.1 μg / mL. Delivery period of 1 antimetabolite; b) Drug-free period; and c) The concentration of antimetabolite in the urine of the said individual is higher than approximately 0.1 μg / mL, the second generation Antagonist delivery period The method according to any one of claims 1 to 24, including the method described above.

26. The concentration of the antimetabolite in the urine was approximately 1 μg / m³ for at least half of the drug-free period. The method according to claim 25, wherein the value is higher than L.

27. Claims 1 to 26 further include the step of administering an effective amount of a second drug to the individual. The method described in any one of the items.

28. The method according to claim 27, wherein the second drug is delivered systemically.

29. The second drug or second chemotherapeutic agent is delivered locally, according to claim 27. method.

30. The antimetabolite and the second drug are delivered via a single delivery device. The method according to claim 29.

31. The second agent is an immunomodulatory agent, according to any one of claims 28 to 30. method.

32. The method according to claim 31, wherein the immunomodulatory agent is an immune checkpoint inhibitor.

33. The aforementioned immune checkpoint inhibitors are PD-L1, CTLA4, PD-L2, and PD-1 B7-H3, B7-H4, HVEM, B and T lymphocyte attenuators (BTLA) Killer inhibitor receptors (KIRs), GAL9, TIM3, A2AR, LAG-3, phosphatidyl Tidylserine, CD27, TNF-α, CD33, Siglec-5, Siglec-7 Immunotherapy selected from the group consisting of Siglec-9 and Siglec-11. The method according to claim 32, wherein the inhibitor is a point protein.

34. The method according to claim 32, wherein the immunomodulatory agent is an agonist of a co-stimulatory immune molecule. 。

35. The aforementioned co-stimulatory immune molecules are CD40, OX40, ICOS, CD28, CD137 / 4- 1BB, CD27, IL-10, TGF-beta, TOR receptor and glucocorticoid The group consisting of TNFR-inducible TNFR-related proteins GITRs is described in claim 34. The method.

36. The present invention relates to any one of claims 27 to 30, wherein the second agent is a second chemotherapeutic agent. The method.

37. The group of chemotherapeutic agents consisting of paclitaxel, docetaxel, and oxaliplatin. The method according to claim 36, selected from the following.

38. The method according to any one of claims 1 to 37, wherein the individual does not receive radiation therapy.

39. The method according to any one of claims 1 to 38, further comprising radiation therapy.

40. The antimetabolite is delivered in a neoadjuvant state, any one of claims 1 to 39. The method used.

41. The antimetabolite is delivered in an adjuvant state, according to any one of claims 1 to 39. Method of description.

42. A third treatment further comprising surgery, wherein delivery of an antimetabolite to the individual is the same as the surgery The method according to any one of claims 1 to 41, which is initiated at a given time.

43. The antimetabolite is delivered into the bladder by an intravesical delivery device, according to claim 1. The method described in any of the above 42.

44. Claim 43, wherein the intravesical device contains 100 mg to 500 mg of gemcitabine. Methods used.

45. The method according to claim 44, wherein the intravesical device comprises 225 mg of gemcitabine. 。

46. The intravesical device comprises a housing configured for intravesical insertion; and an metabolic angiography. The medication includes an antisubstance, the housing holds the medication, and the urine of the lower urinary tract Claim 43, configured to release an antimetabolite in an amount effective for treating urothelial carcinoma. The method described in any of 45.

47. The intravesical drug delivery device is Housing defining the reservoir; A first unit contained within the reservoir, the first unit containing an antimetabolite tt; and A second unit located in the reservoir at a position separate from the first unit. This is a functional drug that promotes the in vivo release of the antimetabolite from the housing. Second unit containing the agent The method according to any one of claims 43 to 46, including the method described in any one of claims 43 to 46.

48. The intravesical drug delivery device contains the antimetabolite and releases it in a controllable manner. , a retaining shape configured to hold the device in the bladder of the individual and the individual Elastically deformable between the deployment shape for the passage of the device through the urethra. The method according to any one of claims 43 to 47, comprising a housing that is capable of performing the same function.

49. The device includes a drug reservoir lumen with a first wall and a second wall as boundaries, The first wall is impermeable to the drug, and the second wall is impermeable to the antimetabolite. The method according to any one of claims 43 to 48, wherein it is permeable.

50. The claim states that the intravesical drug delivery device includes at least two drug reservoir lumens. The method described in any of paragraphs 43 to 49.

51. Claims 43 to 5, wherein the antimetabolite is released from the device by osmotic pressure. The method described in any one of the items in 0.

52. Claims 43 to 51, wherein the antimetabolite is released from the device by diffusion. The method described in any one of the items.

53. Claims 43 to 52, wherein the antimetabolite contained in the housing is in a non-liquid form. One of the methods described above.

54. The non-liquid form may be a tablet, granules, powder, semi-solid, capsule, or a combination thereof. The method according to claim 53, selected from the group.

55. The person according to any one of claims 6 to 54, wherein the urothelial carcinoma of the lower urinary tract is bladder cancer. Law.

56. The method according to claim 55, wherein the bladder cancer is muscle-invasive bladder cancer.

57. The method according to claim 55, wherein the bladder cancer is non-muscle-invasive bladder cancer.

58. Claim 1, wherein the bladder cancer is locally advanced bladder cancer or metastatic bladder cancer. The method described in any of 4 or 6 to 55.

59. The method according to any one of claims 5 to 55, wherein the bladder cancer is carcinoma in situ.

60. The aforementioned bladder cancer is BCG (Calmette-Guérin bacillus) refractory or BCG-resistant cancer. The method according to any one of claims 1 to 55, wherein the cancer is papillary bladder cancer.

61. The method according to any one of claims 1 to 60, wherein the individual is a human.

62. The individual is unsuitable for systemic chemotherapy, as described in any one of claims 1 to 61. The method.

63. The individual having a impaired immune system, according to any one of claims 1 to 62. Law.

64. Claims 1 to 63, wherein the individual has a high level of immune checkpoint protein. The method described in any one of the items.

65. Claims 1 to 63, wherein the individual has a low level of immune checkpoint protein. The method described in any one of the items.

66. The individual has a high level of nucleoside transporters, any one of claims 1 to 65 The method described in section [section number].

67. The individual has a low level of nucleoside transporters, any one of claims 1 to 65 The method described in section [section number].

68. The process further includes a step of determining the gemcitabine / metabolite ratio in urine, and if the ratio is below a threshold The method according to any one of claims 8 to 67, which demonstrates an effective treatment.

69. a) antimetabolites and b) immunomodulatory agents, including urothelium of the lower urinary tract in individuals. A kit for treating cancer, wherein the antimetabolite is for local delivery to the bladder. A kit inside the device.

70. a) an antimetabolite and b) a second drug, comprising urothelial carcinoma of the lower urinary tract in an individual. A kit for treatment, wherein the antimetabolite is used for local delivery to the bladder. The urothelial carcinoma of the lower urinary tract, located within the chair, is a muscle-invasive bladder cancer, kit.

71. The kit according to claim 70, wherein the second drug is an immunomodulator.

72. The kit according to claim 69 or 70, wherein the antimetabolite is gemcitabine.

73. An antimetabolite to an individual's bladder, including a housing containing antimetabolites and immunomodulators. and a delivery device for local delivery of a second drug, wherein the housing is the To provide local release of the antimetabolite and the second drug into the individual's bladder. A delivery device that is configured.

74. The delivery device according to claim 73, wherein the antimetabolite is gemcitabine.

75. The delivery device according to claim 73 or 74, wherein the second drug is an immunomodulator.

76. A method for enhancing the immune response against urothelial carcinoma of the lower urinary tract in an individual, wherein the effective amount The procedure includes the step of administering an antimetabolite to the individual, wherein the antimetabolite is administered locally to the bladder. A method of delivery.

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