Treatment and maintenance therapy methods for bladder cancer using gemcitabine

Abstract

Methods for treating urothelial carcinoma of the lower urinary tract are provided, comprising administering gemcitabine continuously and / or locally to the bladder of an individual during induction and / or maintenance therapy.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 583,394, filed on November 8, 2017, which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] Bladder cancer is a significant medical problem, and the currently available treatment options are insufficient 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 invasion), 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 classified by grade as grade 1 / 3 (well - differentiated), grade 2 / 3 (moderately differentiated), grade 3 / 3 (poorly differentiated). In addition, bladder cancer can be classified by stage as stage 0 - IV (these stages specify the degree to which the cancer invades the bladder wall. Stage 0 is limited to the urothelium, and stage IV indicates cancer that has penetrated the entire thickness of the bladder wall and invaded adjacent organs or tissues). Most bladder cancers are transitional cell carcinomas of epithelial origin and are classified as non - muscle - invasive cancers (NMIBC) that are limited to the inner layer of the bladder. At the initial presentation, most bladder cancers are superficial NMIBC, such as diseases at stages pTa, pTis, and pT1. MIBC is at stages pT2, pT3, and pT4, etc.

[0003] For patients with locally advanced muscle-invasive bladder cancer (MIBC), radical cystectomy is the standard treatment, with chemotherapy administered either before or after surgery (American Cancer Society, 2016b). The National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) also recommend radiotherapy and chemotherapy (if possible) along with resection of bladder tumor (RC) as a potentially curative initial treatment for patients with MIBC (NCCN, 2017; Gakis, 2013). For patients who are not candidates for potentially curative treatment, palliative radiotherapy alone or transurethral resection of bladder tumor (TURBT) alone is recommended.

[0004] Patients unsuitable for definitive treatment aimed at a cure undergo palliative TURBT, either repeated or debulking, in an attempt to limit the local progression of untreated or poorly managed disease. These non-curative strategies are also used to alleviate the exacerbation of pathological symptoms caused by invasive tumors, which often involve bleeding, occlusion, and pain, and frequently require repeated emergency treatment.

[0005] U.S. Patent Application Publications 2012 / 0203203, 2013 / 0158675, 2015 / 0360012, 2015 / 0165177, 2015 / 0165178, 2016 / 0199544, and International Publications 2014 / 145638, 2015 / 200752, and 2011 / 031855 are incorporated herein by reference in their entirety. All other references disclosed herein are incorporated herein by reference in their entirety. [Overview of the project] [Means for solving the problem]

[0006] In some embodiments, methods are provided herein for providing maintenance therapy to an individual, the maintenance therapy being performed after at least one prior therapy, and the maintenance therapy comprising administering gemcitabine to the individual one or more times consecutively over one or more delivery periods in which gemcitabine is delivered locally to the individual's bladder, each delivery period being at least one week, with a rest period of at least one week (e.g., at least one month) between each delivery period, and the individual having urothelial carcinoma of the lower ureter.

[0007] This specification provides a method for treating urothelial carcinoma of the lower ureter in an individual, comprising a) continuous administration of an effective dose of gemcitabine to the individual during an induction phase, and b) continuous administration of an effective dose of gemcitabine to the individual during a maintenance phase, wherein gemcitabine is delivered locally to the individual's bladder, and the induction and maintenance phases are separated by a rest period, with the induction phase lasting approximately 12 weeks.

[0008] This specification also provides a method for bladder preservation in an individual, comprising a) continuous administration of an effective dose of gemcitabine to the individual during the induction phase, and b) continuous administration of an effective dose of gemcitabine to the individual during the maintenance phase, wherein gemcitabine is delivered locally to the individual's bladder, the induction phase and maintenance phase are separated by a rest period, the induction phase is approximately 12 weeks, and the individual has urothelial carcinoma of the lower ureter.

[0009] In some embodiments, gemcitabine is delivered into the bladder by an intravesical device. In some embodiments, the intravesical device contains about 225 mg of gemcitabine.

[0010] In some embodiments, the delivery period is 3 weeks each. In some embodiments, the pause period is approximately 0 to 3 months (for example, 3 months).

[0011] In some embodiments, gemcitabine is delivered at a dose of approximately 1 mg / day to approximately 300 mg / day during the delivery period. In some embodiments, the concentration of gemcitabine in urine is approximately 1 μg / mL to approximately 90 μg / mL during the delivery period. In some embodiments, the average concentration of gemcitabine in urine is approximately 5 to 20 μg / mL during the delivery period.

[0012] In some embodiments, individuals were ineligible for or rejected cisplatin-based chemotherapy.

[0013] In some embodiments, individuals were unsuitable, ineligible for, or refused radical cystectomy.

[0014] In some embodiments, the individual has muscle-invasive bladder cancer.

[0015] In some embodiments, the individual has muscle-non-invasive bladder cancer.

[0016] In some embodiments, the pause period between the introduction phase and the maintenance phase is approximately 1 to 3 months.

[0017] In some embodiments, the maintenance phase includes two or more gemcitabine delivery periods. In some embodiments, the gemcitabine delivery periods during the maintenance phase (also referred to as "maintenance gemcitabine delivery periods") are each interrupted by rest periods of approximately 1 to 3 months.

[0018] In some embodiments, the maintenance gemcitabine delivery period is 1 to 3 weeks. [Brief explanation of the drawing]

[0019] [Figure 1] The research protocol described in Example 1 is shown below. [Modes for carrying out the invention]

[0020] This specification provides a method for treating urothelial carcinoma of the lower ureter as maintenance therapy, comprising topically administering gemcitabine to the bladder. Also provided herein is a method for treating urothelial carcinoma of the lower ureter, comprising topically administering an effective dose of gemcitabine to the bladder during the induction phase and / or during the maintenance phase. In some embodiments, the induction phase comprises two or more delivery periods, such as about two, three, four, or five or more delivery periods. In some embodiments, the delivery periods during the induction phase are continuous. In some embodiments, there are no rest periods or minimum rest periods (such as a rest period of less than one week) between the continuous delivery periods during the induction phase. In some embodiments, the induction phase comprises about four delivery periods (e.g., four consecutive delivery periods), each delivery period being about three weeks (e.g., 18-24 days). In some embodiments, the maintenance phase comprises one or more delivery periods. In some embodiments, each delivery period during the maintenance phase is approximately 3 weeks (e.g., approximately 18-24 days). In some embodiments, the rest period between delivery periods during the maintenance phase is approximately 2 months (e.g., approximately 65-75 days). In some embodiments, urothelial carcinoma is bladder cancer. In some embodiments, bladder cancer is muscle-invasive bladder cancer. In some embodiments, bladder cancer is organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, bladder cancer is T2 or T3 bladder cancer. In some embodiments, bladder cancer is approximately T2 or T3 M0 bladder cancer (e.g., T2 or T3 M0 N0 MIBC).

[0021] While radical cystectomy (RC) remains the standard treatment for MIBC (including organ-limited (OC) MIBC), the natural history of patients who are unable to undergo curative therapy (CIT) is not well understood. The reasons for being unable to undergo CIT are typically underlying comorbidities, frailty, and / or age. A significant proportion of these patients are diagnosed with clinical stage T2–T3 M0 (OC) disease, but these patients do not undergo CIT and ultimately die from these diseases. An analysis of patients diagnosed with T2–T4 MIBC in Sweden between 1997 and 2014 who did not undergo curative therapy (e.g., radical cystectomy) found that this patient population experienced substantial disease-specific mortality, was frequently hospitalized in the last year, and died primarily from bladder cancer progression. This application provides a method for treating urothelial carcinoma of the lower ureter (e.g., bladder cancer, such as MIBC (organ-limited MIBC)) that has shown favorable effects on a patient population, particularly those who are unsuitable, unsuitable, or unwilling to undergo curative therapies such as radical cystectomy. For example, this application demonstrates that frail patients, such as elderly patients, who are unsuitable, unsuitable, or unwilling to undergo radical cystectomy, can adequately tolerate induction therapy consisting of four consecutive periods of gemcitabine delivery, each period of approximately three weeks (e.g., 18-24 days). This application shows that these patients achieved a 50% complete response and an 80% response rate on a per-protocol basis. The provided method also demonstrates that it can effectively improve symptoms associated with bladder cancer and / or previous or current treatments for bladder cancer, such as a reduction in the frequency of hematuria and pain relief. Notably, the method provided demonstrates sustained effects for at least approximately 100 days after induction therapy, and thus provides a basis for the effective maintenance therapy described herein.

[0022] I. Method of the present invention A method for treating urothelial carcinoma of the lower urinary tract is provided herein by administering gemcitabine locally and repeatedly to the bladder over a period of several months. Such a method is useful, for example, as maintenance therapy to prevent recurrence and in bladder preservation protocols.

[0023] As used herein, the terms "continuous" or "continuously" refer to the continuous administration of gemcitabine over a period of time.

[0024] As used herein, the term "individual" refers to mammals such as humans. Individuals include, but are not limited to, humans, cows, horses, cats, dogs, rodents, or primates. In some embodiments, the individual is a human.

[0025] References herein to "about" a value or parameter include (and describe) embodiments that relate to that value or parameter itself. For example, "about 21 days" includes 21 days.

[0026] As used herein, the term "about X to Y" has the same meaning as "from about X to about Y".

[0027] As used herein, the term “effective dose” means an amount of a compound or composition sufficient to treat a particular disorder, condition, or disease, for example, to improve, alleviate, reduce, and / or delay one or more of its symptoms. With respect to cancer or other undesirable cell growth, an effective dose includes an amount sufficient to shrink a tumor and / or reduce the rate of tumor growth (e.g., to inhibit tumor growth), or to prevent or delay other undesirable cell growth. In some embodiments, an effective dose is an amount sufficient to delay progression. In some embodiments, an effective dose is an amount sufficient to prevent or delay the onset and / or recurrence. An effective dose may be administered once or more in the case of cancer, and an effective dose of the drug or composition may (i) reduce the number of cancer cells, (ii) reduce the size of the tumor, (iii) inhibit, delay, slow down, or preferably stop, the invasion of cancer cells into peripheral organs to some extent, (iv) inhibit (i.e., slow down, or preferably stop) tumor metastasis, (v) inhibit tumor growth, (vi) prevent or delay the appearance and / or recurrence of tumors, and / or (vii) alleviate to some extent one or more of the symptoms associated with cancer.

[0028] In some embodiments, the methods provided herein are useful for improving the quality of life of patients. For example, the methods provided herein may be used to provide chronic care to patients who are unable to undergo cystectomy. In some embodiments, the methods provided herein may be used as palliative care. In some embodiments, the herein provides a method for reducing pain in individuals with cancer.

[0029] Medication regimen The following sections describe various embodiments of the administration and therapeutic domain, all of which apply without exception to the methods described herein.

[0030] In some embodiments, methods for maintenance therapy to an individual are provided, which are performed after at least one prior therapy, and which include administering gemcitabine sequentially and topically to the individual's bladder during a delivery period. In some embodiments, methods for providing maintenance therapy to an individual are provided, which are performed after at least one prior therapy, and which include administering gemcitabine to the individual two or more consecutively during two or more delivery periods, each delivery period being interrupted by a rest period of about or at least about one month. In some embodiments, the rest period is about or at least about 1 to 12 months, for example, at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or about 1 year. In some embodiments, the rest period is about 3 months. In some embodiments, the rest period is about 65 to 75 days, for example, 68 to 72 days. In some embodiments, methods for maintenance therapy to an individual are provided, performed after at least one prior therapy, the method comprising administering gemcitabine sequentially and topically to the individual's bladder two or more times over two or more consecutive delivery periods. In some embodiments, there is a rest period of about 0 to 12 months after two or more consecutive delivery periods. In some embodiments, there is a rest period of about 0 to 12 months after two or more consecutive delivery periods. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual has responded to at least one prior therapy (e.g., complete response, partial response, and / or stable disease), and the at least one prior therapy comprises administering gemcitabine sequentially and / or topically to the individual (e.g., into the individual's bladder). In some embodiments, there is a rest period between the prior therapy and the maintenance therapy.In some embodiments, the rest period between prior therapy and maintenance therapy is about or at least about 1 to 12 months, for example, at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or about 1 year. In some embodiments, the rest period between prior therapy and maintenance therapy is about or at least about 3 months. In some embodiments, the individual responds to at least one prior therapy (e.g., complete response, partial response, and / or stable disease). In some embodiments, the individual is selected for maintenance therapy if the individual has a complete response to at least one prior therapy. In some embodiments, the prior response includes at least one induction therapy, which involves administering gemcitabine continuously and topically to the individual's bladder for at least one week (e.g., 12 weeks).

[0031] In some embodiments, methods are provided herein for providing maintenance therapy to an individual, the maintenance therapy being performed after at least one prior therapy, and comprising administering gemcitabine to the individual two or more consecutive times over two or more delivery periods, each delivery period being separated by a rest period of at least one month, and each delivery period being at least about one week. In some embodiments, each delivery period is about one week, two weeks, or three weeks. In some embodiments, each delivery period is about three weeks (e.g., 18-24 days). In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual responds to at least one prior therapy (e.g., complete response, partial response, and / or stable disease), and at least one prior therapy includes administering gemcitabine sequentially and / or topically to the individual (e.g., into the individual's bladder). In some embodiments, the individual responds to at least one prior therapy (e.g., complete response, partial response, and / or stable disease). In some embodiments, the individual is selected for maintenance therapy if the individual has a complete response to at least one prior therapy. In some embodiments, the prior response includes at least one induction therapy, which includes administering gemcitabine sequentially and topically to the individual's bladder for at least one week (e.g., 12 weeks).

[0032] In some embodiments, methods are provided herein for providing maintenance therapy to an individual, the maintenance therapy being performed after at least one prior therapy, and comprising administering gemcitabine to the individual two or more consecutive times over two or more delivery periods, each delivery period being interrupted by a rest period of at least one month, each delivery period being at least about one week, and gemcitabine being delivered locally to the bladder by an intravesical device. In some embodiments, the device contains about 225 mg of gemcitabine. In some embodiments, the delivery periods are interrupted by rest periods of about two months, about three months, about four months, about five months, or about six months. In some embodiments, the rest period is about three months. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual has responded to at least one prior therapy (e.g., complete response, partial response, and / or stable disease), and at least one prior therapy comprises administering gemcitabine sequentially and / or topically to the individual (e.g., into the individual's bladder). In some embodiments, the individual has responded to at least one prior therapy (e.g., complete response, partial response, and / or stable disease). In some embodiments, the individual is selected for maintenance therapy if the individual has a complete response to at least one prior therapy. In some embodiments, the prior response comprises at least one induction therapy comprising administering gemcitabine sequentially and topically to the individual's bladder for at least one week (e.g., 12 weeks).

[0033] In some embodiments, maintenance therapy includes administering approximately 225 mg of gemcitabine twice, approximately every three months. In some embodiments, the method includes administering approximately 225 mg of gemcitabine three, four, five, six, seven times, or over the lifetime of the individual, approximately every three months. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual has responded to prior therapy (e.g., complete response, partial response, and / or stable disease), and the prior therapy includes administering gemcitabine sequentially and / or locally to the individual (e.g., to the individual's bladder).

[0034] In some embodiments, maintenance therapy involves administering approximately 225 mg of gemcitabine to the individual approximately every two months for approximately one year, with gemcitabine delivered topically to the bladder. In some embodiments, approximately 225 mg of gemcitabine is administered to the individual approximately every three months for approximately one year. In some embodiments, approximately 225 mg of gemcitabine is administered to the individual approximately every four months for approximately one year. In some embodiments, approximately 225 mg of gemcitabine is administered to the individual approximately every five months for approximately one year. In some embodiments, approximately 225 mg of gemcitabine is administered to the individual every six months. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle-invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is ineligible for, has refused, or is unsuitable for radical cystectomy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual has responded to prior therapy (e.g., complete response, partial response, and / or stable disease), and the prior therapy comprises administering gemcitabine sequentially and / or topically to the individual (e.g., to the individual's bladder).

[0035] In some embodiments, a gemcitabine-releasing device containing approximately 225 mg of gemcitabine is placed in the individual's bladder for at least one week, approximately every three months, over a period of about one year. In some embodiments, a gemcitabine-releasing device containing approximately 225 mg of gemcitabine is placed in the individual's bladder for two weeks, approximately every three months, over a period of about one year. In some embodiments, a gemcitabine-releasing device containing approximately 225 mg of gemcitabine is placed in the individual's bladder for three weeks, approximately every three months, over a period of about one year. In some embodiments, a gemcitabine-releasing device containing approximately 225 mg of gemcitabine is placed in the individual's bladder for three weeks, approximately every three months, over a period of about one year. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., a cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual has responded to prior therapy (e.g., complete response, partial response, and / or stable disease), and the prior therapy comprises administering gemcitabine sequentially and / or topically to the individual (e.g., into the individual's bladder).

[0036] In some embodiments, the method involves (i) placing a first gemcitabine-releasing intravesical (intravesical) device in the bladder of an individual, wherein the first gemcitabine-releasing intravesical (intravesical) device remains in the bladder and contains approximately 225 mg of gemcitabine; and (ii) removing the first gemcitabine-releasing intravesical (intravesical) device after approximately 3 weeks (e.g., 18-24 days); and (ii) i) placing a second gemcitabine-releasing intravesical (intravesical) device in the individual's bladder approximately three months after the placement of a first gemcitabine-releasing intravesical (intravesical) device in the bladder, the second gemcitabine-releasing intravesical (intravesical) device remaining in the bladder for three weeks and containing approximately 225 mg of gemcitabine; and (iv) removing the second gemcitabine-releasing device. In some embodiments, steps i-iv are repeated approximately every three months for approximately one, two, three years, or the lifetime of the individual. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle-invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is unsuitable, ineligible, or has refused radical cystectomy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual has responded to prior therapy (e.g., complete response, partial response, and / or stable disease), and the prior therapy includes administering gemcitabine sequentially and / or topically to the individual (e.g., to the individual's bladder).

[0037] In some embodiments, methods are provided herein for providing maintenance therapy to an individual, the maintenance therapy being performed after at least one prior therapy, and comprising administering gemcitabine to the individual two or more consecutive times over two or more delivery periods, the gemcitabine being delivered topically to the individual's bladder, each delivery period being at least about one week, and the gemcitabine being delivered at a dose of about 15 mg / day to 100 mg / day during the delivery period. In some embodiments, gemcitabine is delivered at a dose of about 5 mg / day to about 250 mg / day, about 10 mg / day to about 200 mg / day, about 15 mg / day to about 100 mg / day, or about 15 mg / day to about 50 mg / day. In some embodiments, gemcitabine is delivered in doses of approximately 1 mg / day, approximately 5 mg / day, approximately 10 mg / day, approximately 15 mg / day, approximately 20 mg / day, approximately 23 mg / day, approximately 25 mg / day, approximately 30 mg / day, approximately 35 mg / day, approximately 40 mg / day, approximately 45 mg / day, approximately 50 mg / day, approximately 55 mg / day, approximately 60 mg / day, approximately 75 mg / day, approximately 100 mg / day, approximately 125 mg / day, approximately 150 mg / day, approximately 200 mg / day, approximately 250 mg / day, or approximately 300 mg / day. In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual has responded to at least one prior therapy (e.g., complete response, partial response, and / or has a stable disease), and at least one prior therapy includes administering gemcitabine sequentially and / or topically to the individual (e.g., into the individual's bladder). In some embodiments, the individual responds to at least one prior therapy (e.g., complete response, partial response, and / or stable disease). In some embodiments, the individual is selected for maintenance therapy if the individual has a complete response to at least one prior therapy. In some embodiments, the prior response includes at least one induction therapy, which involves administering gemcitabine continuously and topically to the individual's bladder for at least one week (e.g., 12 weeks).

[0038] In some embodiments, methods are provided herein for providing maintenance therapy to an individual, the maintenance therapy being performed after at least one prior therapy, and the maintenance therapy comprising administering gemcitabine to the individual two or more consecutive times over two or more delivery periods in which gemcitabine is delivered topically to the individual's bladder, each delivery period being at least about one week, and the concentration of gemcitabine in the individual's urine being about 1 μg / mL to about 10 μg / mL during the delivery period. In some embodiments, the concentration of gemcitabine in the urine during the delivery period 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 gemcitabine concentration in the urine is approximately 1.0 μg / mL, approximately 5 μg / mL, approximately 10 μg / mL, approximately 15 μg / mL, approximately 20 μg / mL, approximately 25 μg / mL, approximately 30 μg / mL, approximately 40 μg / mL, approximately 50 μg / mL, approximately 60 μg / mL, approximately 70 μg / mL, approximately 80 μg / mL, approximately 90 μg / mL, or approximately 100 μg / mL. In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., a cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual has responded to at least one prior therapy (e.g., complete response, partial response, and / or stable disease), and at least one prior therapy comprises administering gemcitabine sequentially and / or topically to the individual (e.g., into the individual's bladder). In some embodiments, the individual has responded to at least one prior therapy (e.g., complete response, partial response, and / or stable disease). In some embodiments, the individual is selected for maintenance therapy if the individual has a complete response to at least one prior therapy.In some embodiments, the prior response includes at least one induction therapy, which involves administering gemcitabine continuously and topically to the individual's bladder over a period of at least one week (e.g., 12 weeks).

[0039] In some embodiments, the prior therapy includes an induction phase therapy comprising continuous and topical delivery of gemcitabine to the individual's bladder over a period of about 12 weeks, as described herein. In some embodiments, the delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately 3 weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least about 1–2 weeks of the 3-week period, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, for at least about 1–2 weeks of the 3-week period, the average concentration of gemcitabine in the urine is about 5–20 μg / mL. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the prior therapy comprises two or more induction phase therapies. In some embodiments, the two or more induction phase therapies are consecutive (i.e., there is no rest period between the two or more induction phase therapies). In some embodiments, there is a rest period between two or more induction therapy sessions. In some embodiments, the rest period is approximately one month to one year. In some embodiments, the rest period is approximately or at least about one month, about two months, or about three months.

[0040] In some embodiments, the Specified Method for Treating Muscle-Invasive Bladder Cancer in Individuals Unsuitable for or Unsuitable for Cystectomy (such as Radical Cystectomy), comprising the continuous and local delivery of gemcitabine to the individual's bladder over a period of approximately 12 weeks. In some embodiments, the individual is at least approximately 70 years old (e.g., at least approximately 70, approximately 75, approximately 80, approximately 85, or 90 years old). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 M0 MIBC). In some embodiments, the delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately 3 weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least about 1 to 2 weeks out of 3 weeks, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, the average concentration of gemcitabine in the urine is about 5 to 20 μg / mL out of at least about 1 to 2 weeks out of 3 weeks. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes maintenance therapy performed after gemcitabine delivery for about 12 weeks. In some embodiments, there is a rest period of about 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, maintenance therapy includes administering gemcitabine sequentially and topically to the individual's bladder about or at least about 1, about 2 or more times during one, two, or more delivery periods. In some embodiments, each maintenance delivery period is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the maintenance delivery period is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0041] In some embodiments, methods are provided herein for treating muscle-invasive bladder cancer in individuals unsuitable or ineligible for cystectomy (such as radical cystectomy), comprising at least two induction therapies, each induction therapy comprising continuous and local delivery of gemcitabine to the individual's bladder over approximately 12 weeks. In some embodiments, the individual responds to the first induction therapy, such as having a complete response, a partial response, and / or stable disease. In some embodiments, the individual has a partial response or stable disease during or after the first or previous induction therapy. In some embodiments, when the individual has a partial response or stable disease to the first or previous induction therapy, the individual is selected for a second induction therapy. In some embodiments, the individual is at least approximately 70 years old (e.g., at least approximately 70, approximately 75, approximately 80, approximately 85, or 90 years old). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 M0 MIBC). In some embodiments, delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least approximately one to two weeks out of the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of the three weeks, the average concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes approximately 12 weeks of maintenance therapy following gemcitabine delivery. In some embodiments, there is a rest period of approximately 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least about one month, about two months, or about three months. In some embodiments, maintenance therapy includes administering gemcitabine sequentially and topically to the individual's bladder about or at least about one, about two or more times during one, two, or more delivery periods.In some embodiments, each maintenance delivery period is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the maintenance delivery period is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0042] In some embodiments, methods are provided herein for treating muscle-invasive bladder cancer in an individual (such as an individual unsuitable or unsuitable for cystectomy (such as radical cystectomy)), comprising at least two induction therapies and at least one maintenance therapy, each induction therapy comprising continuous and local delivery of gemcitabine to the individual's bladder over approximately 12 weeks. In some embodiments, the two or more induction therapies are interrupted by maintenance therapy. In some embodiments herein, methods are provided for treating muscle-invasive bladder cancer in an individual (such as an individual unsuitable or unsuitable for cystectomy (such as radical cystectomy)), comprising continuous and local delivery of gemcitabine to the individual's bladder over approximately 12 weeks (for example, the delivery comprises four consecutive delivery periods, each delivery period being approximately 3 weeks), wherein the individual has previously received induction therapy and maintenance therapy (such as any of the maintenance therapies described herein). In some embodiments, induction therapy comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks long (e.g., 18–24 days). In some embodiments, during the delivery periods, for at least approximately one to two weeks out of three, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of three, the average concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, at least one maintenance therapy comprises administering gemcitabine sequentially and topically to the individual's bladder approximately or at least approximately one, approximately two or more times during one, two, or more delivery periods. In some embodiments, each delivery period of the maintenance phase is approximately or at least approximately one, approximately two, or approximately three weeks long. In some embodiments, there is a pause between two or more delivery periods (at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, or 12 months).In some embodiments, at least one maintenance phase delivery period is approximately 3 weeks, and during the delivery period, for at least approximately 1 to 2 weeks of that period, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance phase delivery period.

[0043] In some embodiments, a method for bladder preservation in an individual is provided herein, comprising the continuous and local delivery of gemcitabine to the individual's bladder over a period of about 12 weeks. In some embodiments, the individual is at least about 70 years old (e.g., at least about 70, about 75, about 80, about 85, or 90 years old). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 M0 MIBC). In some embodiments, the delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being about 3 weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least about 1–2 weeks of the 3-week period, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, the mean concentration of gemcitabine in the urine is approximately 5–20 μg / mL over at least approximately 1–2 weeks within a 3-week period. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes maintenance therapy administered after gemcitabine delivery for approximately 12 weeks. In some embodiments, there is a rest period of approximately 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least approximately 1 month, approximately 2 months, or approximately 3 months. In some embodiments, maintenance therapy includes administering gemcitabine sequentially and topically to the individual's bladder approximately or at least approximately 1, approximately 2 or more times during one, two, or more delivery periods. In some embodiments, each delivery period of the maintenance phase is approximately or at least approximately 1 week, approximately 2 weeks, or approximately 3 weeks. In some embodiments, the maintenance delivery period is approximately 3 weeks, and during the delivery period, for at least 1 to 2 weeks of that period, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period of the maintenance phase.

[0044] In some embodiments, methods are provided herein for alleviating symptoms of bladder cancer in an individual, comprising continuous and topical delivery of gemcitabine to the individual's bladder over a period of about 12 weeks. In some embodiments, alleviating symptoms includes reducing the occurrence of obstruction. In some embodiments, alleviating symptoms includes reducing the frequency and / or degree of hematuria, i.e., bleeding in the urine. In some embodiments, alleviating symptoms includes reducing the frequency or degree of pain. In some embodiments, symptoms are alleviated over a period of about or at least about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 100 days, about 120 days, about 150 days, about 180 days, or about 200 days after the commencement of gemcitabine delivery. In some embodiments, the individual is at least about 70 years old (e.g., at least about 70 years, about 75 years, about 80 years, about 85 years, or 90 years). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 M0 MIBC). In some embodiments, delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least approximately one to two weeks out of the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of the three weeks, the average concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes approximately 12 weeks of maintenance therapy following gemcitabine delivery. In some embodiments, there is a rest period of approximately 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least about one month, about two months, or about three months. In some embodiments, maintenance therapy includes administering gemcitabine sequentially and topically to the individual's bladder about or at least about one, about two or more times during one, two, or more delivery periods.In some embodiments, each maintenance delivery period is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the maintenance delivery period is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0045] In some embodiments, methods are provided herein for improving the quality of life of an individual with bladder cancer, comprising continuous and local delivery of gemcitabine to the individual's bladder over a period of about 12 weeks. In some embodiments, improving the quality of life includes alleviating symptoms associated with bladder cancer, such as reducing the occurrence of obstruction, reducing the frequency and / or severity of hematuria, reducing the frequency or severity of pain, and / or reducing the need for emergency procedures. In some embodiments, symptoms are alleviated over a period of about or at least about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 100 days, about 120 days, about 150 days, about 180 days, or about 200 days after the commencement of gemcitabine delivery. In some embodiments, the individual is at least about 70 years old (e.g., at least about 70 years, about 75 years, about 80 years, about 85 years, or 90 years). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, delivery includes four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks long (e.g., 18–24 days). In some embodiments, during the delivery period, for at least approximately one to two weeks out of the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of the three weeks, the average concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes maintenance therapy administered after gemcitabine delivery for approximately 12 weeks. In some embodiments, there is a rest period of approximately 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least approximately one month, approximately two months, or approximately three months. In some embodiments, maintenance therapy involves administering gemcitabine sequentially and topically to the individual's bladder about or at least about one, about two or more times during a one, two, or more delivery period.In some embodiments, each maintenance delivery period is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the maintenance delivery period is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0046] In some embodiments, a method is provided herein for treating urothelial carcinoma of the lower ureter in an individual with a history of hematuria, comprising continuous and local delivery of gemcitabine to the individual's bladder over a period of about 12 weeks. In some embodiments, the hematuria includes chronic hematuria, gross hematuria, incidental hematuria, and / or recurrent gross hematuria. In some embodiments, the individual has reduced hematuria symptoms (such as reduced frequency and / or degree of hematuria) after delivery of gemcitabine. In some embodiments, the individual has reduced hematuria symptoms (such as reduced frequency and / or degree of hematuria) for at least about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 120 days, about 150 days, about 180 days, or about 200 days after delivery of gemcitabine. In some embodiments, the individual is at least about 70 years old (such as at least about 70 years, about 75 years, about 80 years, about 85 years, or 90 years). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least approximately one to two weeks out of three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of three weeks, the mean concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes maintenance therapy for approximately 12 weeks following gemcitabine delivery. In some embodiments, there is a rest period of about 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, maintenance therapy includes administering gemcitabine sequentially and topically to the individual's bladder about or at least about 1, about 2 or more times during one, two, or more delivery periods.In some embodiments, each maintenance delivery period is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the maintenance delivery period is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0047] In some embodiments, a method is provided herein for preventing the progression of bladder cancer in an individual, comprising the continuous and local delivery of gemcitabine to the individual's bladder over a period of about 12 weeks. In some embodiments, the prevention of progression continues for about or at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. In some embodiments, the individual is at least about 70 years old (e.g., at least about 70 years, about 75 years, about 80 years, about 85 years, or 90 years). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, the delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being about 3 weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least about 1 to 2 weeks out of 3 weeks, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, the average concentration of gemcitabine in the urine is about 5 to 20 μg / mL out of at least about 1 to 2 weeks out of 3 weeks. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes maintenance therapy performed after gemcitabine delivery for about 12 weeks. In some embodiments, there is a rest period of about 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, maintenance therapy includes administering gemcitabine sequentially and topically to the individual's bladder about or at least about 1, about 2 or more times during one, two, or more delivery periods. In some embodiments, each delivery period in the maintenance phase is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the delivery period in the maintenance phase is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL).In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0048] In some embodiments, a method for treating urothelial carcinoma of the lower ureter in an individual involves continuous and local delivery of gemcitabine to the individual's bladder over a period of approximately 12 weeks. In some embodiments, prevention of progression continues for approximately or at least approximately 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the individual is at least approximately 70 years old (e.g., at least approximately 70, 75, 80, 85, or 90 years old). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, delivery comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately 3 weeks (e.g., 18–24 days). In some embodiments, during the delivery period, for at least about 1 to 2 weeks out of 3 weeks, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, the average concentration of gemcitabine in the urine is about 5 to 20 μg / mL out of at least about 1 to 2 weeks out of 3 weeks. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method further includes maintenance therapy performed after gemcitabine delivery for about 12 weeks. In some embodiments, there is a rest period of about 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the rest period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, maintenance therapy includes administering gemcitabine sequentially and topically to the individual's bladder about or at least about 1, about 2 or more times during one, two, or more delivery periods. In some embodiments, each maintenance delivery period is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the maintenance delivery period is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0049] In some embodiments, a method is provided for maintenance therapy performed after at least one prior therapy for an individual having urothelial carcinoma of the lower ureter, the method comprising administering gemcitabine sequentially and topically to the individual's bladder one, two, or more (e.g., two or more) delivery periods, each delivery period being at least one week, with a rest period of at least one month between each delivery period. In some embodiments, the individual is at least about 70 years old (e.g., at least about 70, about 75, about 80, about 85, or 90 years old). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, at least one prior therapy involves the continuous and topical administration of gemcitabine to the individual's bladder, and this therapy comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18–24 days). In some embodiments, during the delivery period of the prior therapy, for at least approximately one to two weeks out of the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of the three weeks, the average concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, there is a rest period of approximately 12 weeks between the prior therapy and the maintenance therapy. In some embodiments, the rest period is at least approximately one month, approximately two months, or approximately three months. In some embodiments, each maintenance delivery period is approximately or at least approximately one week, approximately two weeks, or approximately three weeks. In some embodiments, the maintenance delivery period is approximately three weeks, and during the delivery period, for at least approximately one to two weeks within the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0050] In some embodiments, a method is provided for treating urothelial carcinoma of the lower ureter in an individual, the method comprising a) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during an induction phase of about 12 weeks, and b) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during a maintenance phase, the induction and maintenance phases being separated by a rest period. In some embodiments, the rest period is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, or about 12 months. In some embodiments, the individual is at least about 70 years old (at least about 70 years, about 75 years, about 80 years, about 85 years, or 90 years, etc.). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, the induction phase includes the continuous and topical administration of gemcitabine to the individual's bladder, comprising four delivery periods (e.g., four consecutive delivery periods), each delivery period lasting approximately three weeks (e.g., 18–24 days). In some embodiments, during the delivery periods of the induction phase, for at least approximately one to two weeks out of the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of the three weeks, the average concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the rest period is at least approximately one month, approximately two months, or approximately three months. In some embodiments, maintenance therapy involves administering gemcitabine sequentially and topically to the individual's bladder about or at least about one, about two or more times during one, two, or more delivery periods. In some embodiments, each delivery period of the maintenance phase is about or at least about one week, about two weeks, or about three weeks. In some embodiments, the delivery period of the maintenance phase is about three weeks, and during the delivery period, for at least about one to two weeks of the three weeks, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL).In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0051] In some embodiments, a method for bladder preservation in an individual having urothelial carcinoma of the lower ureter is provided, the method comprising a) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during an induction phase of about 12 weeks, and b) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during a maintenance phase, the induction and maintenance phases being separated by a rest period. In some embodiments, the rest period is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, or about 12 months. In some embodiments, the individual is at least about 70 years old (at least about 70 years, about 75 years, about 80 years, about 85 years, or 90 years, etc.). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, the induction phase includes the continuous and topical administration of gemcitabine to the individual's bladder, comprising four delivery periods (e.g., four consecutive delivery periods), each delivery period lasting approximately three weeks (e.g., 18–24 days). In some embodiments, during the delivery periods of the induction phase, for at least approximately one to two weeks out of the three weeks, the concentration of gemcitabine in the individual's urine is at least approximately 0.1 μg / mL (e.g., approximately 0.1 μg / mL to approximately 90 μg / mL). In some embodiments, for at least approximately one to two weeks out of the three weeks, the average concentration of gemcitabine in the urine is approximately 5–20 μg / mL. In some embodiments, approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the rest period is at least approximately one month, approximately two months, or approximately three months. In some embodiments, maintenance therapy involves administering gemcitabine sequentially and topically to the individual's bladder about or at least about one, about two or more times during one, two, or more delivery periods. In some embodiments, each delivery period of the maintenance phase is about or at least about one week, about two weeks, or about three weeks. In some embodiments, the delivery period of the maintenance phase is about three weeks, and during the delivery period, for at least about one to two weeks of the three weeks, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL).In some embodiments, approximately 225 mg of gemcitabine is administered during each maintenance delivery period.

[0052] In some embodiments, a method is provided for treating urothelial carcinoma of the lower ureter (such as bladder cancer, e.g., MIBC) in an individual, the method comprising: a) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during an induction phase comprising four consecutive delivery periods, each delivery period being approximately three weeks; and b) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during a maintenance phase comprising at least two delivery periods, each delivery period being approximately three weeks, with a rest period of at least approximately two months between the two or more delivery periods of the maintenance phase, the induction phase and the maintenance phase being separated by a rest period of at least approximately three months. In some embodiments, a method is provided for treating urothelial carcinoma of the lower ureter (such as bladder cancer, e.g., MIBC) in an individual, the method comprising: a) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during an induction phase comprising four consecutive delivery periods, each delivery period being approximately 3 weeks; and b) administering an effective dose of gemcitabine to the individual's bladder continuously and topically during a maintenance phase comprising two or more delivery periods, each delivery period being approximately 3 weeks, with a rest period of approximately 2 months between the two or more delivery periods of the maintenance phase, the induction and maintenance phases being separated by a rest period of approximately 3 months. In some embodiments, the individual is at least approximately 70 years old (e.g., at least approximately 70, approximately 75, approximately 80, approximately 85, or 90 years old). In some embodiments, the individual has a defective immune system. In some embodiments, the individual has cT2 or cT3 organ-specific MIBC (e.g., N0 MIBC). In some embodiments, during the induction and / or maintenance delivery periods, the concentration of gemcitabine in the individual's urine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL) for at least about 1 to 2 weeks of the 3-week delivery period. In some embodiments, the mean concentration of gemcitabine in the urine is about 5 to 20 μg / mL for at least about 1 to 2 weeks of the 3-week delivery period. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period of the induction and / or maintenance period.

[0053] In some embodiments, a method of bladder preservation in an individual comprises administering an effective dose of gemcitabine to the individual, the gemcitabine being delivered locally to the individual's bladder over a period of approximately 12 weeks, and the individual having cT2 bladder cancer. In some embodiments, a method of bladder preservation in an individual comprises administering an effective dose of gemcitabine to the individual, the gemcitabine being delivered locally to the bladder over four delivery periods (such as four consecutive delivery periods), each delivery period being approximately 3 weeks (such as 18-24 days), and the individual having cT2 bladder cancer. In some embodiments, a method of bladder preservation in an individual comprises administering an effective dose of gemcitabine to the individual, the gemcitabine being delivered locally to the bladder over four delivery periods (such as four consecutive delivery periods), each delivery period being approximately 3 weeks (such as 18-24 days), with approximately 225 mg of gemcitabine being administered during each delivery period, and the individual having cT2 bladder cancer. In some embodiments, the individual has organ-specific muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, two adjacent delivery periods are separated by a rest period. In some embodiments, the rest period is about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or less than 1 day or less.

[0054] In some embodiments, a method for treating urothelial carcinoma of the lower ureter in an individual comprises administering an effective dose of gemcitabine to the individual, the gemcitabine being delivered topically to the individual's bladder over a period of approximately 12 weeks, and the individual having cT2 bladder cancer. In some embodiments, a method for treating urothelial carcinoma of the lower ureter in an individual comprises administering an effective dose of gemcitabine to the individual, the gemcitabine being delivered topically to the bladder over four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately 3 weeks (e.g., 18-24 days), and the individual having cT2 bladder cancer. In some embodiments, a method for treating urothelial carcinoma of the lower ureter in an individual comprises administering an effective dose of gemcitabine to the individual, the gemcitabine being delivered locally to the bladder during four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18–24 days), with approximately 225 mg of gemcitabine administered during each delivery period, and the individual having cT2 bladder cancer. In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, two adjacent delivery periods are separated by a rest period. In some embodiments, the rest period is approximately 7 days, approximately 6 days, approximately 5 days, approximately 4 days, approximately 3 days, approximately 2 days, or less than 1 day or less.

[0055] In some embodiments, the methods provided herein may be used as a method for bladder preservation in an individual. In some embodiments, the method for bladder preservation in an individual comprises administering an effective dose of gemcitabine to the individual during an induction phase and administering an effective dose of gemcitabine to the individual during a maintenance phase, wherein gemcitabine is delivered locally to the bladder, and the induction and maintenance phases are separated by a rest period, the induction phase being approximately 12 weeks. In some embodiments, the individual does not undergo radical cystectomy. In some embodiments, the rest period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, or approximately 6 months. In some embodiments, the induction phase comprises administering approximately 900 mg of gemcitabine to the individual. In some embodiments, the individual has muscle-non-invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-specific muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the induction phase involves implanting gemcitabine-releasing devices every three weeks for a total of 12 weeks, each device releasing 225 mg of gemcitabine. In some embodiments, the rest period is approximately 2–3 months, e.g., approximately 65–75 days, e.g., 68–27 days. The maintenance phase involves placing a gemcitabine-releasing device containing 225 mg of gemcitabine in the individual's bladder every three months for one year. In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to the induction phase therapy (e.g., complete response, partial response, and / or stable disease).

[0056] In this specification, a method for bladder preservation in an individual comprises administering an effective dose of gemcitabine to the individual during the induction phase and administering an effective dose of gemcitabine to the individual during the maintenance phase, wherein the gemcitabine is delivered locally to the bladder, the induction phase and the maintenance phase are separated by a rest period, the induction phase is approximately 12 weeks, and the individual has cT2 bladder cancer. In this specification, a method for bladder preservation in an individual comprises administering an effective dose of gemcitabine to the individual during the induction phase and administering an effective dose of gemcitabine to the individual during the maintenance phase, wherein the gemcitabine is delivered locally to the bladder, the induction phase comprises four delivery periods (such as four consecutive delivery periods), each delivery period is approximately 3 weeks (such as 18-24 days), and the maintenance phase comprises administering gemcitabine to the individual approximately every 3 months, the induction phase and the maintenance phase are separated by a rest period, and the individual has cT2 bladder cancer. In this specification, a method for bladder preservation in an individual comprises administering an effective dose of gemcitabine to the individual during an induction phase and administering an effective dose of gemcitabine to the individual during a maintenance phase, wherein gemcitabine is delivered locally to the bladder, the induction phase comprises four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18-24 days), with approximately 225 mg of gemcitabine administered during each delivery period, the maintenance phase has three-week delivery periods every three months (i.e., maintenance delivery periods), with approximately 225 mg of gemcitabine administered during each maintenance delivery period, the induction and maintenance phases are separated by rest periods, and the individual has cT2 bladder cancer. In some embodiments, the maintenance phase is approximately one year, two years, three years, five years, ten years, throughout the individual's lifetime, or until disease progression or toxicity. In some embodiments, the rest period is approximately 2-3 months, for example, approximately 65-75 days, for example, 68-72 days. In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to induction therapy (e.g., complete response, partial response, and / or stable disease). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC).

[0057] This specification also provides a method for treating urothelial carcinoma of the lower ureter in an individual, comprising administering an effective dose of gemcitabine to the individual during an induction phase and an effective dose of gemcitabine to the individual during a maintenance phase, wherein the gemcitabine is delivered locally to the bladder, and the induction and maintenance phases are separated by a rest period, with the induction phase being approximately 12 weeks. In some embodiments, the method for treating urothelial carcinoma of the lower ureter in an individual comprises administering an effective dose of gemcitabine to the individual during an induction phase and an effective dose of gemcitabine to the individual during a maintenance phase, wherein the gemcitabine is delivered locally to the bladder, and the induction and maintenance phases are separated by a rest period, with the induction phase being approximately 84 days. In some embodiments, the rest period is 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle-invasive bladder cancer. In some embodiments, the individual is unsuitable for or rejects cisplatin-based chemotherapy. In some embodiments, the individual is unsuitable for, rejects, or rejects radical cystectomy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to induction therapy (e.g., complete response, partial response, and / or stable disease).

[0058] This specification also provides a method for treating urothelial carcinoma of the lower ureter in an individual, the method comprising administering an effective dose of gemcitabine to the individual during an induction phase and an effective dose of gemcitabine to the individual during a maintenance phase, the gemcitabine being delivered locally to the bladder, the induction phase and the maintenance phase being separated by a rest period, the induction phase being approximately 12 weeks, and the individual having cT2 bladder cancer. This specification also provides a method for treating urothelial carcinoma of the lower ureter in an individual, the method comprising administering an effective dose of gemcitabine to the individual during an induction phase and administering an effective dose of gemcitabine to the individual during a maintenance phase, the gemcitabine being delivered locally to the bladder, the induction phase comprising four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18-24 days), and the maintenance phase comprising administering gemcitabine to the individual approximately every three months, the induction and maintenance phases being separated by rest periods, the induction phase being approximately 12 weeks, and the individual having cT2 bladder cancer. This specification also provides a method for treating urothelial carcinoma of the lower ureter in an individual, the method comprising administering an effective dose of gemcitabine to the individual during an induction phase and administering an effective dose of gemcitabine to the individual during a maintenance phase, the gemcitabine being delivered locally to the bladder, the induction phase comprising four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18-24 days), and the maintenance phase comprising administering gemcitabine to the individual approximately every three months, the induction and maintenance phases being separated by rest periods, the induction phase being approximately 12 weeks, and the individual having cT2 bladder cancer.This specification also provides a method for treating urothelial carcinoma of the lower ureter in an individual, the method comprising administering an effective dose of gemcitabine to the individual during the induction phase and administering an effective dose of gemcitabine to the individual during the maintenance phase, the gemcitabine being delivered locally to the bladder, the induction phase comprising four delivery periods (e.g., four consecutive delivery periods), each delivery period being approximately three weeks (e.g., 18-24 days), and the maintenance phase comprising administering gemcitabine to the individual approximately every three months. The induction phase involves administering the drug to the body, and consists of four delivery periods (e.g., four consecutive delivery periods), each lasting approximately three weeks (e.g., 18-24 days), during which approximately 225 mg of gemcitabine is administered. The maintenance phase consists of three-week delivery periods every three months (i.e., maintenance delivery periods), during which approximately 225 mg of gemcitabine is administered. The induction and maintenance phases are separated by rest periods, and the individual has cT2 bladder cancer. In some embodiments, the maintenance phase lasts for approximately one, two, three, five, or ten years, throughout the individual's lifetime, or until disease progression or toxicity. In some embodiments, the rest period is approximately two to three months, e.g., approximately 65 to 75 days, e.g., 68 to 72 days. In some embodiments, the rest period is approximately three months. In some embodiments, the individual responds to induction therapy (e.g., complete response, partial response, and / or stable disease). In some embodiments, the individual has organ-specific muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC).

[0059] In some embodiments, a method for treating urothelial carcinoma of the lower ureter in an individual comprises administering an effective dose of gemcitabine to the individual during an induction phase and administering an effective dose of gemcitabine to the individual during a maintenance phase, wherein gemcitabine is delivered locally to the bladder, and the induction and maintenance phases are separated by a rest period, the induction phase being 12 weeks and the rest period being approximately 3 months. In some embodiments, the induction phase comprises administering approximately 900 mg of gemcitabine to the individual over 12 weeks. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle-invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is ineligible for, has refused, or is unsuitable for radical cystectomy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-specific muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to induction therapy (e.g., complete response, partial response, and / or stable disease).

[0060] In some embodiments, the method involves administering gemcitabine to an individual over a 12-week period, followed by a rest period of approximately 2-3 months, followed by a maintenance period, during which gemcitabine is administered to the individual every 3 months for at least one year, with gemcitabine delivered topically to the bladder. In some embodiments, the method involves administering gemcitabine to an individual over a 12-week period, followed by a rest period of approximately 2-3 months, followed by a maintenance period, with gemcitabine delivered topically to the bladder, with the maintenance period involving the administration of approximately 225 mg of gemcitabine to the individual every 3 months for approximately one year. In some embodiments, the maintenance period is approximately one year, approximately two years, approximately three years, approximately five years, approximately ten years, or throughout the individual's lifetime. In some embodiments, the maintenance period involves delivering gemcitabine two, three, four, five, six times, or throughout the individual's lifetime, every approximately 3 months. In some embodiments, the maintenance delivery period is approximately 3 weeks (e.g., 18-24 days). In some embodiments, the maintenance delivery period is approximately 1 week, 2 weeks, or 3 weeks. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle-invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is ineligible for, has refused, or is unsuitable for radical cystectomy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period is approximately 3 months. In some embodiments, individuals respond to a 12-week course of gemcitabine (including complete response, partial response, and / or stable disease).

[0061] In some embodiments, methods are provided herein for treating urothelial carcinoma of the lower ureter in an individual, comprising an induction phase and a maintenance phase, wherein the induction phase comprises administering approximately 900 mg of gemcitabine to the individual over 12 weeks, and the maintenance phase comprises administering approximately 225 mg of gemcitabine to the individual every approximately 3 months for at least 1 year, the gemcitabine being delivered locally to the bladder, and the induction and maintenance phases are separated by a rest period of approximately 2-3 months. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 M0 MIBC. In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to induction therapy (e.g., complete response, partial response, and / or stable disease).

[0062] In some embodiments, a method is provided herein for treating urothelial carcinoma of the lower ureter in an individual, comprising an induction phase and a maintenance phase, wherein the induction phase comprises administering approximately 900 mg of gemcitabine to the individual over 12 weeks, and the maintenance phase comprises administering approximately 225 mg of gemcitabine to the individual every approximately 3 months for at least 1 year, the gemcitabine being delivered locally to the bladder, the induction phase and the maintenance phase being separated by a rest period of approximately 2-3 months, and the individual having cT2 bladder cancer. In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 M0 MIBC. In some embodiments, methods are provided herein for treating urothelial carcinoma of the lower ureter in an individual, comprising an induction phase and a maintenance phase, wherein the induction phase comprises administering approximately 900 mg of gemcitabine to the individual over 12 weeks, and the maintenance phase comprises administering approximately 225 mg of gemcitabine to the individual every approximately 3 months for at least 1 year, the gemcitabine being delivered topically to the bladder, the induction and maintenance phases being separated by a rest period of approximately 2-3 months, and the individual having cT3 bladder cancer. In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to the induction phase therapy (e.g., complete response, partial response, and / or stable disease).

[0063] In some embodiments, the induction phase includes four delivery periods (e.g., four consecutive delivery periods), each lasting approximately three weeks (e.g., 18–24 days). In some embodiments, the induction phase includes four delivery periods (e.g., four consecutive delivery periods), each lasting approximately three weeks (e.g., 18–24 days), with approximately 225 mg of gemcitabine administered during each delivery period. In some embodiments, an intravesical device containing approximately 225 mg of gemcitabine is inserted into the bladder every three weeks over a 12-week period during the induction phase. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle-invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is ineligible for, has refused, or is unsuitable for radical cystectomy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual has organ-specific muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to induction therapy (e.g., complete response, partial response, and / or stable disease).

[0064] In some embodiments, a method is provided herein for treating urothelial carcinoma of the lower ureter in an individual, comprising an induction period comprising four delivery periods (such as four consecutive delivery periods), each delivery period being approximately three weeks (such as 18-24 days), a rest period, and a maintenance period comprising two or more gemcitabine delivery periods, separated by approximately three months, during which approximately 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the individual has cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period is approximately three months. In some embodiments, the individual responds to induction therapy (e.g., complete response, partial response, and / or stable disease).

[0065] In some embodiments, the maintenance phase is a treatment phase following at least one primary therapy. In some embodiments, the primary therapy is an induction therapy comprising administering gemcitabine. In some embodiments, the maintenance therapy comprises two or more gemcitabine delivery periods, separated by periods of at least one month, each delivery period comprising administering about 225 mg of gemcitabine, which is delivered topically to the bladder. In some embodiments, the maintenance phase delivery periods are separated by periods of about two months, three months, four months, five months, or six months. In some embodiments, the maintenance phase comprises two or more delivery periods, separated by periods of about three months, each delivery period comprising administering about 225 mg of gemcitabine to the individual, which is delivered topically to the individual's bladder. In some embodiments, the maintenance phase comprises placing a gemcitabine-releasing device containing about 225 mg of gemcitabine in the individual's bladder approximately every three months for about one year. In some embodiments, the maintenance delivery period is approximately 1 week, 2 weeks, or 3 weeks, respectively. In some embodiments, the maintenance delivery period is approximately 3 weeks (e.g., 18–24 days), respectively. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle-invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is ineligible for, has refused, or is unsuitable for radical cystectomy. In some embodiments, the rest period is approximately 3 months. In some embodiments, the individual responds to at least one first-line therapy (e.g., complete response, partial response, and / or stable disease).

[0066] Patient group The methods provided herein are useful for treating a range of individuals having urothelial carcinoma. For example, in some embodiments, urothelial carcinoma is bladder cancer. In some embodiments, bladder cancer is locally advanced bladder cancer. In some embodiments, the cancer is metastatic bladder cancer. In some embodiments, bladder cancer is muscle-invasive bladder cancer. In some embodiments, bladder cancer is muscle-non-invasive bladder cancer. In some embodiments, bladder cancer is carcinoma in situ. In some embodiments, bladder cancer is BCG (Calmette-Guérin bacillus) refractory 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 cancer is stage I, stage II, stage III, or stage IV bladder cancer. In some embodiments, bladder cancer is high-grade invasive papillary urothelial carcinoma. In some embodiments, bladder cancer is high-grade non-invasive urothelial carcinoma. In some embodiments, the bladder cancer is a highly malignant, multifocal, invasive urothelial carcinoma. In some embodiments, the bladder cancer is cT2 or cT3. In some embodiments, the bladder is cT2 with carcinoma in situ.

[0067] In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals ineligible for cisplatin-based neoadjuvant therapy, the method comprising topically administering gemcitabine to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals rejecting cisplatin-based neoadjuvant therapy, the method comprising topically administering gemcitabine to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals having cT2 disease and not possessing high-risk features such as lymphatic invasion (LVI), hydronephrosis, or associated carcinoma in situ (CIS), the method comprising topically administering gemcitabine to the bladder. In some embodiments, this specification provides a method for treating bladder cancer (e.g., MIBC) in an individual who is scheduled to undergo radical cystectomy but is ineligible for cisplatin-based neoadjuvant therapy, the method comprising topically administering gemcitabine to the bladder. In some of these embodiments, the individual has cT2 cancer. In some embodiments, the individual has organ-limited muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC). In some embodiments, the individual has cT2 M0 N0 MIBC.

[0068] In some embodiments, individuals are ineligible for cisplatin-based therapy due to comorbidities such as poor performance status, poor renal function, hearing loss, peripheral neuropathy, and heart disease. In some embodiments, individuals are ineligible for cisplatin-based therapy because they do not have one or more high-risk features such as lymphatic infiltration (LVI), hydronephrosis, and associated carcinoma in situ (CIS).

[0069] Accordingly, in some embodiments, methods are provided herein for treating individuals who are unsuitable for cisplatin-based therapy, the method comprising administering gemcitabine to the individual approximately every three months, the gemcitabine being delivered topically to the individual's bladder over a period of at least one week. In some embodiments, approximately 225 mg of gemcitabine is administered approximately every three months for approximately one year, approximately two years, approximately four years, or over the patient's lifetime. In some embodiments, gemcitabine is delivered continuously over a period of approximately one week, approximately two weeks, or approximately three weeks during the delivery period.

[0070] In some of these embodiments, the method involves administering approximately 225 mg of gemcitabine to an individual for 3 weeks at approximately 3-month intervals over approximately 2 years. In some of these embodiments, the method involves administering approximately 225 mg of gemcitabine to an individual for 3 weeks at approximately 3-month intervals over approximately 3 years. In some of these embodiments, the method involves administering approximately 225 mg of gemcitabine to an individual for 3 weeks at approximately 3-month intervals over the lifetime of the individual. In some embodiments, the method includes a 12-week induction period followed by a maintenance period.

[0071] Until now, neoadjuvant therapy, followed by radical cystectomy or bladder removal, has been the standard treatment for muscle-invasive bladder cancer. Individuals unsuitable for radical cystectomy undergo palliative transurethral resection of bladder cancer (TURBT) to attempt to limit the local progression of untreated or poorly treated disease. Such treatment can temporarily address hematuria, pain, and urgent local symptoms, but is not used for curative purposes. Therefore, in one embodiment, the present invention provides a method for treating bladder cancer (e.g., MIBC) in individuals unsuitable or unqualified for cystectomy by topical administration of gemcitabine to the bladder.

[0072] In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals unsuitable for cystectomy, comprising delivering gemcitabine locally to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals unsuitable for cystectomy, comprising delivering gemcitabine locally to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in frail individuals, comprising delivering gemcitabine locally to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals unable to tolerate radical cystectomy, comprising delivering gemcitabine locally to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals without removing the individual's bladder, comprising delivering gemcitabine locally to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals who are unsuitable or unqualified for cystectomy, the methods comprising topically delivering gemcitabine to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals where the bladder cancer is metastatic bladder cancer. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals having cT2-cT3 disease (e.g., cT2-cT3 M0 disease), the methods comprising topically delivering gemcitabine to the bladder.

[0073] In some embodiments, methods are provided herein for treating muscle-invasive bladder cancer in individuals who are unsuitable or ineligible for cystectomy, the method comprising continuous and topical delivery of gemcitabine to the individual's bladder for at least about one week every three months. In some of these embodiments, gemcitabine may be delivered chronically or continuously over the individual's lifetime to improve the individual's quality of life. In some embodiments, about 225 mg of gemcitabine is administered every three months for about one year, about two years, about four years, or over the patient's lifetime. In some embodiments, gemcitabine is delivered continuously over about one week, about two weeks, or about three weeks during the delivery period.

[0074] In some embodiments, individuals were unsuitable for or refused cisplatin-based chemotherapy. In some embodiments, individuals were unsuitable for, unqualified for, or refused radical cystectomy.

[0075] In some embodiments, the individual is unsuitable for radical cystectomy under National Comprehensive Cancer Network (NCCN) guidelines. For example, the individual may be unsuitable for radical treatment due to frailty. Prior to this procedure, such individuals typically received palliative radiotherapy (3.5 Gy / fraction - 10 treatments; or 7 Gy / fraction - 7 treatments; TURBT; or no treatment) without chemotherapy. In some embodiments, the individual is unsuitable for platinum-based chemotherapy. In some embodiments, chemotherapy prior to radiotherapy is not recommended for the individual. In some embodiments, the individual does not receive radical treatment or systemic chemotherapy. In some embodiments, the individual has cT2-cT3 disease (e.g., cT2-cT3 M0 disease).

[0076] In some embodiments, individuals may not be able to withstand radical cystectomy according to American Society of Anesthesiology (ASA) guidelines. For example, individuals who cannot withstand radical cystectomy may be deemed medically unsuitable for surgery requiring general or epidural anesthesia.

[0077] In other embodiments, the individual may lack postoperative implantation or personnel as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists. Under these guidelines, an individual is considered frail if they exhibit abnormal levels of independence in daily living, severe malnutrition, cognitive impairment, or comorbidities with a cumulative illness rating scale for geriatrics (CISR-G) grade of 3–4.

[0078] The method of the present invention also provides significant therapeutic effects compared to standard treatment regimens that seek bladder removal. The present invention also has the advantage of being useful as a bladder-preserving protocol for individuals who are eligible for cystectomy but choose not to undergo cystectomy. The method results in a significant improvement in the quality of life of individuals who may be able to retain their bladder after having bladder cancer compared to currently available treatments. Accordingly, in some embodiments, a bladder-preserving method for treating bladder cancer (e.g., MIBC) in an individual is provided, comprising the topical delivery of gemcitabine to the bladder. In some embodiments, a method for treating bladder cancer (e.g., MIBC) in an individual without removing the bladder is provided, comprising the topical delivery of gemcitabine to the bladder. Also provided herein is a method for treating bladder cancer (e.g., MIBC) in an individual who would otherwise undergo cystectomy, the method comprising the topical delivery of gemcitabine to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals who are eligible for cystectomy but choose not to undergo it, the methods comprising topically delivering gemcitabine to the bladder. In some embodiments, methods are provided herein for bladder preservation as an alternative to radical cystectomy, the methods comprising topically delivering gemcitabine to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in individuals who choose not to undergo cystectomy, the methods comprising topically delivering gemcitabine to the bladder. In some embodiments, methods are provided herein for preserving an individual's bladder, comprising topically delivering gemcitabine to the bladder. In some embodiments, methods are provided herein for treating bladder cancer (e.g., MIBC) in an individual without removing the individual's bladder, the methods comprising topically delivering gemcitabine to the bladder. In some embodiments, methods are provided herein for treating CT2 urothelial carcinoma in individuals who would otherwise undergo cystectomy, the methods comprising locally delivering gemcitabine to the bladder.

[0079] In some embodiments, this method is particularly suitable for treating individuals who are CT2 patients who would typically undergo radical cystectomy followed by neoadjuvant therapy. This method results in local / regional control of the disease, such as nodules, and can therefore be used for long-term treatment in this bladder-preserving population. This method also results in freedom from invasive recurrence, good long-term bladder function, and a low rate of salvage cystectomy, all of which are important in an elderly, relatively frail population with bladder cancer, with an average age of 70 years.

[0080] In some embodiments, this method is applicable to subjects with a history of hematuria (such as chronic hematuria, gross hematuria, recurrent gross hematuria, or recurrent hematuria). This method reduces and / or controls the symptoms of hematuria over a period of approximately 200 days.

[0081] In some embodiments, the individual has muscle-invasive bladder cancer (MIBC). In some embodiments, the individual has non-muscle-invasive bladder cancer (NMIBC).

[0082] In some embodiments, the individual has non-metastatic (M0) bladder cancer (e.g., MIBC). In some embodiments, the individual has N0 bladder cancer (e.g., MIBC). In some embodiments, the individual has N1, N2, or N3 bladder cancer (e.g., MIBC). In some embodiments, the individual has a cT2 or cT3 bladder tumor (e.g., MIBC). In some embodiments, the individual has Ta, Tis, T1, T2 (e.g., T2a and / or T2b), T3 (e.g., T3a and / or T3b), or T4 (e.g., T4a and / or T4b) bladder cancer (e.g., MIBC). In some embodiments, the individual has N0 and M0 bladder cancer (e.g., MIBC). In some embodiments, the individual has cT2, N0, and M0 MIBC. In some embodiments, the individual has cT3, N0, and M0 MIBC.

[0083] In some embodiments, the individual is at least about 60, 65, 70, 75, 80, 85, or 90 years old. In some embodiments, the individual has a defective immune system.

[0084] In some embodiments, the individual is human.

[0085] II. Intravesical (intravesical) devices Device shape In some embodiments, the methods provided herein involve administering gemcitabine using an intravesical (intravesical) device. In some embodiments, the intravesical (intravesical) device includes a placement shape and a retaining shape. For example, the device may be elastically deformable between a relatively straight or non-coiled shape (placement shape) suitable for insertion into the individual's bladder through a lumen (e.g., urethra) and a retaining shape suitable for retaining the device within the bladder. For the purposes of this disclosure, terms such as “relatively expanded shape,” “relatively large external shape,” or “retaining shape” generally mean any shape suitable for retaining the device in the intended implantation location, including, but not limited to, a pretzel shape or other coiled shape (e.g., bielliptic or overlapping coil) suitable for retaining the device within the bladder. The retaining shape ensures that the device is taken up in the urine during urination and not excreted. Similarly, terms such as “relatively small external shape” or “placement shape” generally refer to any shape suitable for placing a drug delivery device within the body, including, but not limited to, a linear or elongated shape suitable for placing the device through a working channel of a catheter, cystoscope, or other placement device positioned within the urethra. In some embodiments, the drug delivery device may naturally assume a relatively expanded shape and may be deformed into a relatively small external shape manually or with the help of an external device for insertion into the body. For example, the external device may be an inserter configured for transurethral insertion. Once placed, the intravesical (intravesical) device may spontaneously, i.e., naturally return to its original relatively expanded shape and be retained within the body. In some embodiments, the device behaves like a spring and deforms in response to a compressive load (e.g., deforming the device into the placement shape), but spontaneously returns to the retaining shape when the load is removed.

[0086] In some embodiments, the deformation function of the intravesical (intravesical) device described in the preceding paragraph may be provided by including a shape-retaining frame (i.e., “retaining frame”) in the device, such as those disclosed in the above-mentioned patent application publications incorporated herein by reference. In some embodiments, the device may include a retaining frame lumen, in which the retaining frame may be an elastic wire or a superelastic alloy such as Nitinol. The retaining frame may be configured to spontaneously return to a retaining shape, such as a “pretzel” shape or another coil shape, such as those disclosed in the previously incorporated patent application. Specifically, the retaining frame may hold the device in the body, for example, in the bladder. The retaining shape prevents the device from being taken into the urine and excreted when the individual urinates. For example, the retaining frame may allow the device to be introduced into the body in a relatively small external shape, and to return to a relatively expanded shape once the device is inside the body, and may have elastic limits and moduli that prevent the device from taking a relatively small external shape in the body in response to expected forces such as detrusor muscle contraction and hydrodynamic forces associated with urination. Therefore, once deployed, the device can be retained within the individual's bladder, limiting, or preventing, accidental discharge.

[0087] In some other embodiments, the deformation function of an intravesical (intravesical) device may be provided by forming the device housing with an elastic polymer that is at least partially thermally shaped.

[0088] The material used to form the device body (i.e., housing) may be at least partially elastic or flexible so that the device can move between the placement shape and the retaining shape. When the device is in the retaining shape, the retaining frame portion may tend to be located inside the drug reservoir portion as shown in the figure, but in other cases, the retaining frame portion may be located inside, outside, above, or below the drug reservoir portion. The material used to form the device body may be permeable to water, so that when the device is placed in the bladder, a solubilizing fluid (e.g., urine) can enter the drug reservoir portion and solubilize gemcitabine, immunomodulators, additional therapeutic agents, functional agents, or combinations thereof in non-liquid form contained in the drug reservoir. For example, silicone or another biocompatible elastomer material may be used. In other embodiments, the device body may be formed at least partially of a non-permeable material.

[0089] In some embodiments, the device body is made of an elastic, biocompatible polymer material. This material may be non-absorbent or absorbent. Examples of non-absorbent materials include poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene), and other fluorinated polymers, as well as synthetic polymers selected from poly(siloxane). Examples of absorbent materials, specifically biodegradable or biodegradable polymers, include poly(amide), poly(ester), poly(esteramide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo-poly(amino acid), poly(glycerol-sevacate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(caprolactone), poly(caprolactone) (PC) derivatives, amino alcohol-based poly(esteramide) (PEA) and poly(octanediol citrate) (POC), as well as synthetic polymers selected from other curable bioabsorbable elastomers. PC-based polymers may require additional crosslinking agents such as lysine diisocyanate or 2,2-bis(e-caprolactone-4-yl)propane to obtain rubbery elasticity. Copolymers, mixtures, and combinations of the above materials may also be used.

[0090] In some embodiments, the device body comprises silicone, thermoplastic polyurethane, ethyl vinyl acetate (EVA), or a combination thereof. In some embodiments, the device body comprises two different thermoplastic materials, one of which is hydrophilic thermoplastic polyurethane and is drug-permeable, and the other is drug-impermeable. The drug-impermeable material may be selected from the group consisting of hydrophilic polyurethane, hydrophilic polyester, and hydrophilic polyamide. The device body may comprise an annular tube formed by an extrusion or co-extrusion process using one or more of these materials, as described in U.S. Patent Publication 2016 / 0310715.

[0091] Drug core In embodiments in which antimetabolites are delivered from an intravesical (intravesical cavity) drug delivery device, the drug may be contained within the device in various forms that can be adapted to a specific mechanism by which the device controls the release of the drug into the fluid in the bladder (e.g., urine). In some embodiments, the drug may be supplied in a solid, semi-solid, or other non-liquid form, which may be advantageous as it may facilitate the stable storage of the drug before use of the device, and may be advantageous as it may allow for a smaller volume of drug filling in the device to be stored than may occur if the drug were contained in the form of a liquid solution. In one embodiment, the non-liquid form may be selected from tablets, granules, powders, semi-solids (e.g., ointments, creams, pastes, or gels), capsules, and combinations thereof. In one embodiment, the drug may be in the form of multiple tablets, such as the minitablets described in U.S. Patent No. 8,343,516.

[0092] For example, the antimetabolite may take the form of a suspension, solution, or emulsion in an oily or aqueous medium, and may contain formulations such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form obtained by sterile isolation of a sterile solid or by freeze-drying from a solution, for use in a suitable medium, such as sterile, pyrogen-free water.

[0093] In one embodiment, gemcitabine is formulated with one or more excipients, including a viscosity enhancer, to control the release of solubilized gemcitabine from a release opening in the device housing. In another embodiment, the device reservoir contains both gemcitabine and a viscosity enhancer, but they are not co-formulated and are instead provided, for example, as separate tablets in separate regions within the reservoir. Suitable viscosity enhancers, including but not limited to polyethylene oxide (PEO), are known in the pharmaceutical field. In some variations of the embodiments, the viscosity enhancer may be provided, for example, with urea or another penetrating agent and formulated, for example.

[0094] In one embodiment, gemcitabine is administered to an organism together with a solubility enhancer. In one embodiment, the solubility enhancer is urea. In one embodiment, the urea is provided in tablet or other solid form and is filled together with gemcitabine into the drug reservoir of an intravesical (intravesical) drug delivery device. Depending on the device, the urea may also function as an osmotic agent to facilitate the generation of osmotic pressure within the drug reservoir. In certain embodiments, gemcitabine and the osmotic agent are configured as separate tablets (or other solid forms) positioned in different regions of the drug reservoir, as described in International Publication No. 2015 / 026813 (Lee et al.), which is incorporated herein by reference.

[0095] In some embodiments, the device may include drug reservoir lumens. In some of these embodiments, each drug reservoir lumen may hold one or more drug tablets or other solid drug units. In one embodiment, the device holds about 10 to 100 cylindrical drug tablets (such as mini-tablets) in a number of separate drug reservoir lumens. In certain embodiments, each mini-tablet may have a diameter of about 1.0 to about 3.3 mm, for example, about 1.5 to about 3.1 mm, and a length of about 1.5 to about 4.7 mm, for example, about 2.0 to about 4.5 mm.

[0096] Drug Housing The release of gemcitabine from the intravesical (intravesical) devices described herein may be driven and controlled by different mechanisms of action. In various embodiments, the drug may be released from the intravesical (intravesical) drug delivery device by diffusion through the walls of the drug housing, by diffusion through one or more defined openings within the walls of the drug housing, by osmotic pressure through openings within the drug housing, by osmotic pressure through one or more temporarily formed microchannels, by erosion of the formulation in contact with urine in the bladder, or by a combination thereof. In some embodiments, drug release is controlled by drug diffusion through a drug-permeable polymer or matrix component defining a portion of the device housing. In one embodiment, the device includes a drug-permeable polymer component.

[0097] The size of the housing, including the wall thickness, may be selected based on, in particular, the volume of the drug (and functional agent, if present) formulation to be contained, the desired drug delivery rate from the device body / housing, the intended implantation site of the device in the body, the desired mechanical integrity of the device, the desired release rate or permeability to water and urine, the desired introduction time before the start of the initial release, and the desired method or route of insertion into the body. In embodiments where the housing is a tube, the tube wall thickness may be determined based on the mechanical properties and water permeability of the tube material. This is because a tube wall that is too thin may not have sufficient mechanical integrity, while a tube wall that is too thick may result in an undesirably long introduction time for the initial drug release from the device and / or may not have sufficient flexibility to allow delivery through the urethra or other narrow body lumens.

[0098] In some embodiments, the housing may be an elongated annular tube having an inner diameter of about 2 mm to about 5 mm. The drug and functional agent (if present) may be solid tablets having substantially the same diameter as the inner diameter of the elongated annular tube. In some embodiments, the housing holds one or more first drug units containing a drug and one or more second drug units that facilitate the release of this drug. One or more tablets of the first unit may fill a length of about 1 cm to about 3 cm of the lumen of the tube, and one or more tablets of the second unit may fill a length of about 10 cm to about 15 cm of the lumen of the tube. In one embodiment, the ratio of the volume of the first unit to the volume of the second unit is about 0.05 to about 0.5. Other lengths and ratios of tablet fills are conceivable.

[0099] In some embodiments, the housing may be an elongated annular tube having a wall thickness of approximately 0.1 mm to approximately 0.4 mm, such as 0.2 mm. The housing material may include one or more biocompatible elastomers. The housing material may be selected such that the housing has a durometer of 25A to 80A, for example, 25A, 50A, 65A, 70A, or 80A.

[0100] In various embodiments, the intravesical (intravesical) device may continuously or intermittently release the drug to achieve an intravesical concentration of the drug that produces a sustained therapeutically effective concentration of the drug in the urine within the bladder, as described in the methods provided herein. For example, the release may occur over periods of 1 hour to 1 month, e.g., 2 hours to 2 weeks, 6 hours to 1 week, 24 hours to 72 hours, etc. In certain embodiments, the intravesical (intravesical) device may release gemcitabine in amounts of 1 mg / day to 1000 mg / day, e.g., 20 mg / day to 300 mg / day, or 25 mg / day to 300 mg / day. In certain embodiments, these release rates are provided over the treatment period described herein. In certain embodiments, these release rates are provided over a treatment period of 14 to 21 days.

[0101] Penetration and diffusion systems Following in vivo configuration, the device releases the drug. As described above, release can occur due to an osmotic gradient between the inside and outside of the device, or due to the drug passing through one or more orifices or passages within the device under osmotic pressure. Release can also occur by diffusion, thereby the drug passing through one or more orifices or passages within the device and / or the drug permeable walls of the device, due to a drug concentration gradient between the inside and outside of the device. Combinations of these release modes within a single device are possible and, in some embodiments, are preferred to achieve an overall drug release profile that cannot be readily achieved with any of the individual modes.

[0102] In some embodiments where the device contains a drug in solid form, drug elution from the device occurs after the drug has been dissolved within the device. Body fluids enter the device, come into contact with the drug, solubilize it, and then the dissolved drug diffuses from the device or flows out of the device by osmosis or diffusion. For example, if the device is placed in the bladder, the drug may be solubilized upon contact with urine. In certain embodiments, a water-permeable wall portion of the housing is permeable to the drug in an aqueous solution, and the solubilized drug is released through the wall portion, also referred to herein as “transwall diffusion.” After the device is embedded, water or urine permeates through the wall and enters the reservoir, solubilizing the functional agent and / or drug. The drug then diffuses directly through the wall at a controlled rate due to the drug concentration gradient inside and outside the device. For example, the housing and / or any water or drug-permeable wall portion may be silicone, thermoplastic polyurethane, ethylene-co-vinyl acetate (EVA), or a combination thereof.

[0103] In some embodiments, the intravesical (intravesical) device may contain a unit concentration of gemcitabine of about 225 mg. In some of these embodiments, the device may be configured to deliver about 100 to about 225 mg of gemcitabine (e.g., about 140 mg, about 160 mg, about 180 mg, about 200 mg, or about 220 mg) to an individual over a period of three weeks.

[0104] In certain embodiments, the drug delivery device may include a delivery system such as those described in International Publication No. 2014 / 145638 and U.S. Patent Application Publication No. 2016 / 0310715, which are incorporated herein by reference in their entirety. In some embodiments, the drug delivery device includes a housing having a closed drug reservoir lumen bounded by a first wall structure and a hydrophilic second wall structure, and a formulation containing gemcitabine housed within the drug reservoir lumen, wherein the first wall structure is permeable or impermeable to water and impermeable to the drug, and the second wall structure is permeable to gemcitabine.

[0105] In some embodiments, the device housing has walls that border and define the device's drug reservoir, made of a first material acting as a first wall structure and a second material acting as a second wall structure, so that drug release essentially occurs only through the second material. In one embodiment, the device does not include an opening, and drug release occurs solely by diffusion through the second wall structure. As used herein, the terms “drug-impermeable” and “water-impermeable” mean that the wall structure is substantially impermeable to drug or water, so that drug or water is not released essentially through the wall structure over the therapeutic release period. For use in the bladder, it is desirable that the device be flexible (i.e., easily bendable and soft to the touch) during detrusor contraction. This is to avoid or reduce discomfort and irritation to the patient. Therefore, the durometer of the first and second materials of the structure is a design consideration, and the proportion of high-durometer material may be limited in constructing a device housing of a given size while ensuring suitability within the bladder. For example, Tecophilic® thermoplastic polyurethane (Lubrizol Corp.) can have a Shore hardness of over 70A, such as 80A to 65D, while silicone tubes can have a Shore hardness of 50A to 70A. Therefore, it may be advantageous to use a combination of these two different polymer materials rather than fabricating the entire device with a second material that is water-swellable, hydrophilic, and drug-permeable.

[0106] The arrangement of the first and second wall structures can take various forms. In certain embodiments, the first wall structure is a cylindrical tube and the second wall structure is an end wall disposed at at least one end of the cylindrical tube, or the first and second wall structures are adjacent to each other and together form a cylindrical tube. That is, drug release is controlled by drug diffusion through a drug-permeable component defining a portion of the closed device housing. The drug-permeable wall structure may be positioned, sized, and have material properties to provide controlled drug diffusion from the device at a desired rate. In one embodiment, the drug-permeable wall may include a disk optionally sandwiched and stabilized between an inner washer and an outer washer within the lumen of the tube at or near the end of the tube. In another embodiment, the drug-permeable wall is a portion of the side wall of the tubular housing, or a portion of an end plug located at the end of the tubular housing.

[0107] The length and width, for example, of the wall portion formed of a permeable material, are selected to provide a water flow of a desired velocity to a reservoir defined by the device housing. In one embodiment, the width of the permeable wall portion may be quantified by the arc angle defining the wall when viewed in a cross section perpendicular to the lumen axis. The permeable region of the device housing may be controlled to provide a selected area, and therefore velocity, of permeable water absorption, while advantageously maintaining the favorable overall dimensions and elasticity of a device formed of a more suitable biocompatible elastomer. Advantageously, by forming the device housing by a co-extrusion process, structural variations in the permeable region can be fabricated in conventional co-extruded devices by selecting processing parameters, thereby beneficially providing the ability to cost-effectively manufacture multiple structural device configurations. In some embodiments, the length of the permeable region extends along only a portion of the total length of the device. Thus, in such embodiments, a larger arc angle can be used for the permeable region, while at the same time, the drug release rate can be maintained at a desired level over a long period of time.

[0108] In some embodiments, the walls may have varying thicknesses around the perimeter; for example, the drug-permeable portion may be thinner than the drug-impermeable portion. Furthermore, thinner drug-permeable wall structures may be positioned at various locations relative to adjacent, thicker drug-impermeable wall structures. In some embodiments, drug release is controlled by drug diffusion through drug-permeable components defining a portion of the closed device housing. The drug-permeable wall structures may be positioned, dimensioned, and have material properties to provide controlled drug diffusion at a desired rate from the device.

[0109] In some embodiments, the drug delivery device comprises a housing comprising a first wall structure and a second wall structure adjacent to each other and together forming a tube defining a drug reservoir lumen, and a drug contained within the drug reservoir lumen, wherein (i) the second wall structure, or both the first and second wall structures, are permeable to water, (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, so that the drug can be released in vivo by diffusion through the second wall structure, (iii) the second wall structure comprises less than 90 percent of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube, and (iv) the first wall structure comprises a first polyurethane composition.

[0110] In some embodiments, the device comprises an elongated elastic housing having a drug reservoir lumen extending between a first closed end and a second closed end, and a drug contained within the drug reservoir lumen, wherein (i) the housing comprises a first annular segment entirely formed of a first material that is impermeable to the drug, and a second annular segment at least partially formed of a second material that is permeable to the drug and configured to release the drug in vivo by diffusion through the second material within the second annular segment, and (ii) the first annular segment has a first end integrally formed with and connected to the first end of the second annular segment.

[0111] In some embodiments, the walls defining the drug reservoir lumen may have varying thicknesses. Housings with walls of different thicknesses may improve the flexibility, compressibility, or both of the housing. Different wall thicknesses may also help in securing solid drug units within the drug reservoir lumen.

[0112] In some embodiments, the intravesical (intravesical) device body or housing may include openings (e.g., at opposite ends of an annular tube) that require sealing after the drug reservoir is filled with a drug filler during the assembly process. Any of these defined openings or ends of the housing, such as monolithic housings and modular housing units, may be sealed if it is desirable to block the opening. This sealing may be achieved by a sealing material or structure. The sealing structure may be formed from biocompatible materials, such as metals like stainless steel, polymers like silicone, ceramics, or sapphire, or adhesives, or combinations thereof. The sealing material or structure may be biodegradable or biodegradable. In one embodiment, a medical-grade silicone adhesive or other adhesive is filled into the opening in a fluid or effective form and then cured within the housing opening to seal the opening. In some embodiments, the housing includes one or more predetermined openings for releasing drugs from the device. These drug release openings are not predetermined openings that are sealed. In other embodiments, the housing does not include predetermined drug release openings.

[0113] In some embodiments, the device releases a drug without having a predetermined drug release opening (i.e., an orifice). The release of a drug from a device without a predetermined drug release opening may be driven by diffusion or osmosis. Examples of such suitable “orifice-free” release systems are described in International Publication 2014 / 144066 (TB130) and U.S. Patent Application Publication 2014 / 0276636 (TB134), which are incorporated herein by reference.

[0114] In certain embodiments, the drug delivery device may include a penetration system as described in U.S. Patent Application Publication 2016 / 0199544, U.S. Patent No. 8,679,094, and U.S. Patent Publication 2016 / 0008271, which are incorporated herein by reference.

[0115] In some embodiments, the device comprises a housing defining a reservoir, a first unit housed within the reservoir comprising a drug, and a second unit housed within the reservoir at a different location from the first unit comprising a functional agent that facilitates the in vivo release of the drug from the housing. In some embodiments, the first unit comprises one or more solid tablets comprising at least one drug (e.g., gemcitabine), and the second unit comprises one or more solid tablets (e.g., including a penetrating agent such as urea). In some embodiments, the housing is in the form of an elongated elastomer tube having a lumen (i.e., a reservoir) in which all the solid tablets of the first and second units are aligned and housed. The diameter of the solid tablets may be substantially the same as the diameter of the lumen.

[0116] If osmotic release is the desired drug release mode, the functional agent in the second unit may include a penetrating agent that facilitates the osmotic release of the drug. For example, the penetrating agent may have a higher solubility than the drug so that the penetrating agent facilitates solubilization and / or subsequent drug release. This is advantageous as it allows for the delivery of low-solubility or other drugs from osmotic delivery-based devices, which are typically delivered by diffusion alone. The device may exhibit an introduction period during which a sufficient amount of the functional agent and / or drug is solubilized to achieve an osmotic gradient.

[0117] Subsequently, the device may exhibit a zero-order emission rate over a long period, followed by a reduced non-zero-order emission rate over a decay period. The desired delivery rate can be achieved by controlling / selecting various parameters of the device, including, but not limited to, the surface area and thickness of the permeable wall, the water permeability of the material used to form the wall, the shape, size, number, and arrangement of the openings, and the solubility profile of the drug and functional agent.

[0118] The devices described herein may also be configured to release a drug by diffusion alone or in combination with osmotic release. The devices may also be configured to allow the solubilized drug to pass through one or more openings in or within the housing.

[0119] Alternatively, or in combination with a permeable wall portion, the housing may include at least one opening configured to allow fluid to enter the reservoir in vivo. The housing may also include one or more openings or passages configured to allow solubilized drugs to pass through.

[0120] In some embodiments of the infiltration system, the device housing comprises a first elastomer material that is permeable to water and a second elastomer material that is impermeable to water, and both materials are selected to be impermeable to the drug contained within the housing.

[0121] Erosion-based system In some embodiments, which may be used with tablets containing low-solubility drugs, the drug is supplied in tablet form fixed to the device with the tablet surface exposed, resulting in drug release from the device occurring by controlled erosion / dissolution, as described in U.S. Patent No. 9,107,816. In some embodiments, the device may comprise a modular housing. The modular housing is typically formed of at least two separate housing units, each unit housing at least one solid drug unit. The material from which each housing unit is formed defines at least one drug reservoir lumen capable of housing a solid drug unit. The drug reservoir lumen may have one or more defined openings. For example, the drug reservoir lumen may have two opposing openings that expose the corresponding, opposing end faces of at least one solid drug unit housed therein. In certain embodiments, at least two separate housing units within the modular housing are connected directly or indirectly by a retaining frame. In some embodiments, the modular housing units may be arranged on a retaining frame to form a “bracelet” design. The device may have one or more housing units. The number of housing units may be limited only by the size of the retaining frame to which they are connected.

[0122] In some embodiments, one or more of the separate housing units include a retaining frame lumen through which a shared retaining frame extends. In certain embodiments, the retaining frame lumen and drug reservoir lumen of each housing unit are arranged parallel to each other. In certain embodiments, the retaining frame lumen and drug reservoir lumen of each housing unit are arranged perpendicular to each other. In further embodiments, the retaining frame lumen and drug reservoir lumen of each housing unit are arranged at angles other than 0° (parallel) and 90° (perpendicular), for example, 5°, 10°, 30°, 45°, 60°, or 85°. In further embodiments, the devices described herein include two or more housing units having at least two of the following configurations: (1) the retaining frame lumen and drug reservoir lumen are arranged substantially parallel to each other; (2) the retaining frame lumen and drug reservoir lumen are arranged substantially perpendicular to each other; or (3) the retaining frame lumen and drug reservoir lumen are arranged at angles other than 0° (parallel) and 90° (perpendicular).

[0123] Integrated silicone drug delivery system In some embodiments, the device may include an elastic polymer drug matrix as described in International Publication No. 2015 / 200752, which is incorporated herein by reference in its entirety.

[0124] Device with multiple emission parts In certain embodiments, the device includes at least two drug-releasing portions, at least one of which releases the drug at a different rate than the other, as described in International Publication No. 2011 / 031855, which is incorporated herein by reference in its entirety. The releasing portions may achieve different release rates, in particular, by having different configurations, by accommodating different formulations, by using different release mechanisms, or by a combination thereof. The releasing portions may be combined to achieve a desired release profile. For example, the device may include releasing portions that exhibit different induction or delay times before the start of initial release, release the drug at different rates or according to different release curves after the start of release, or release the drug over different periods before the drug fill is substantially depleted, or a combination thereof. Heterogeneous releasing portions may be combined to achieve a desired release profile from the drug delivery device, such as exhibiting a relatively short initial delay time followed by sustained release at a relatively constant rate over a long period.

[0125] In some embodiments, the device is filled with a drug in the form of numerous solid drug tablets, which may be smaller in size than conventional drug tablets. Since the device controls the release of the drug into the body, the drug itself may contain little to no excipients that control drug release. Instead, any excipients present in the drug tablets may be present primarily or entirely to facilitate the tableting process or in vivo solubilization. Thus, the device may provide a high drug filler by volume or weight, but may also be small enough for minimally invasive in vivo placement.

[0126] The drug housing also allows for the release of the drug, either in liquid or semi-solid form, at the time of implantation or after in vivo solubilization. The walls may be formed of a drug-permeable material that allows the drug to flow out through the drug housing along its entire length. The walls may also be formed of a material that is semi-permeable to the drug, at least partially, depending on the drug form. For example, the walls may be permeable to the drug in one form, such as a charged form, but not in another form, such as an uncharged form (e.g., base form versus salt form). The walls may also include one or more openings or passages that are formed to completely penetrate, allowing the drug to exit the drug housing.

[0127] The drug housing contains a number of solid drug tablets, which are arranged in series within the housing and sealed inside using a sealing structure such as a plug that closes the inlet openings at both ends of the drug housing. Gaps or cracks formed between adjacent drug tablets allow the tablets to move relative to each other, so that the device is flexible despite being filled with solid drug tablets.

[0128] The drug portion may have any combination of the features or configurations described herein. That is, openings may be provided, omitted, replaced by through holes, or enhanced with additional openings or through holes; the housing may have porous walls having an open-cell structure or an closed-cell structure; and one or more degradable timing structures or release control structures may be associated with the housing or any combination thereof.

[0129] The drug tablets may be aligned in any arrangement other than series arrangement, depending on the configuration of the drug housing. The drug tablets may fill any part of the drug housing other than the entire drug housing as described. To fill any part of the drug housing that is not filled with drug tablets, a filler material such as silicone adhesive or air may be used to increase the buoyancy of the device. The composition of the drug tablets may be the same or may differ along the device. The drug may also be in a form other than drug tablets, such as other liquid, semi-solid, or solid forms (e.g., granules).

[0130] In certain embodiments, the drug delivery device includes at least two separate or isolated drug portions associated with a single retaining portion. Each drug portion may be a separate drug housing associated with the retaining portion, or the drug portions may be separate regions within a single drug housing associated with the retaining portion.

[0131] Each drug portion may be defined by a portion of the wall of the drug housing and at least one partition structure that separates the drug portion from a second drug portion. The partition structure may be a plug inserted into the housing, such as a cylinder, sphere, or disc, and may be fixed in place depending on its size or by using an adhesive. The partition structure may also be part of the housing and may be formed directly inside it by casting or the like.

[0132] A device having at least two distinct parts may be suitable for the controlled release of at least two drug fillers from a corresponding number of drug reservoirs. The two distinct parts may have the same or different configurations as those described herein. The two drug fillers may be the same or different from each other in particular in terms of content, such as active ingredient content or excipient content, form, such as salt form or base form, state, such as liquid, semi-solid or solid state, or combinations thereof. Thus, the two distinct parts may release the two drug fillers simultaneously or at different times, or in combination thereof, at the same or different rates, via the same or different release mechanisms.

[0133] For example, one drug portion may be configured to release the drug packing relatively quickly after implantation, another drug portion may be configured to experience an introduction time before the start of release, or a combination thereof. The start of release of the two packings in different drug portions may be stepwise. Examples of rapid-release drug portions include drug portions that act as relatively fast-acting permeation pumps, such as silicone tubes with relatively thin walls, drug portions that are filled with a drug in a rapid-release form, such as a liquid or specially formulated solid, drug portions associated with a relatively fast-acting degradable timing structure, or a combination thereof. Thus, the device may release the drug during the initial acute phase and during the maintenance phase.

[0134] As another example, one drug portion may be configured to release its drug filler at a relatively faster rate than other drug fillers. For example, one drug portion may contain a drug filler with low water solubility for diffusion release that begins relatively quickly after implantation, and another drug portion may contain a drug filler with high water solubility for osmotic release after an introduction period. As yet another example, one drug portion may contain a liquid drug filler for rapid release through an opening with a rapidly degradable timing membrane, and another drug portion may contain another drug filler in the form of a solid tablet for delayed release after solubilization in vivo. As yet another example, one drug portion may have a relatively rigid wall, and another drug portion may have a closed-cell porous wall that can increase the release rate by increasing the osmotic flow of water or drug through the wall, or by increasing the osmotic flow of water or drug through the wall.

[0135] The release portions may be combined to achieve a desired release profile. For example, the device may include release portions that exhibit different induction or delay times before the start of the initial release, release the drug at different rates or according to different release curves after the start of release, or release the drug over different periods before the drug fill is substantially depleted, or a combination thereof. Different release portions may be combined as a whole to achieve a desired release profile from the drug delivery device, such as exhibiting a relatively short initial delay time followed by sustained release at a relatively constant rate over a long period.

[0136] By combining multiple distinct drug parts within a single device, the device may exhibit a desired release profile for an antimetabolite. The release profile from the device as a whole may be the sum of the release profiles of the distinct parts. For example, the first part may exhibit a minimum delay time before release initiation, the second part may exhibit a short introduction period for the development of an osmotic gradient, and the third part may exhibit a longer delay before initiation for the degradable structure to dissolve or degrade. Once release is initiated from any one of the parts, the release rate may be relatively zero-order for a long period, followed by a decay period. It should be noted that three distinct parts are an example, and any number or combination of distinct parts may be used to achieve a desired release profile.

[0137] Since different drug portions are simply separate regions within a single tubular housing, the device can be advantageously relatively simple to construct and assemble, and further different drug portions exhibit different release profiles due to different drug fillers, opening arrangements, and degradable timing structures. In other embodiments where the drug portions use, for example, different materials, thicknesses, or porous cell structures for the walls, the housings may differ along their length, or separate drug housings may be used. Thus, controlled release can be achieved in a variety of ways.

[0138] gel In another embodiment, the coating substance may be applied to the bladder wall within the bladder cavity (e.g., to the area of ​​the urinary tract within the bladder), and the coating substance comprises gemcitabine or another drug and one or more excipient materials that promote adhesion of the coating substance to the bladder wall and result in sustained and controlled drug release over the course of treatment. The coating substance may be a mucosal adhesive formulation such as a gel, ointment, cream, paste, film, emulsion gel, tablet, polymer, or a combination thereof. Examples of mucosal adhesive polymers include hydrogels or hydrophilic polymers, polycarbophils (i.e., Carbopol, etc.), chitosan, polyvinylpyrrolidone (PVP), lectins, polyethylene glycolated polymers, cellulose, or a combination thereof. Preferred celluloses include methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), or a combination thereof. The coating substance may contain a penetration enhancer. Non-limiting examples of penetration enhancers include dimethyl sulfoxide (DMSO), sodium carboxymethylcellulose (NaCMC), lipids, surfactants, or combinations thereof. The coating material may be placed within the bladder so as to engage with the bladder wall.

[0139] The coating material may be placed in the bladder using a placement device. The placement device may be any device designed to travel through the body's natural lumen and reach the intended implantation site. For placement in the bladder, the placement device is sized and shaped to reach the bladder through the patient's urethra. The placement device may be a known device such as a catheter or cystoscope, or a specially designed device. The placement device is used to place the coating material in the body and is subsequently removed from the body, leaving the entire coating material implanted in the body. Once implanted in this manner, the coating material may release the drug into the body over a long period of time. Using equivalent procedures, any of the devices or drugs described herein may be placed in other parts of the body through other natural lumen. For example, a liquid drug or formulation may be placed in the bladder using a placement device, by passing the placement device through the urethra.

[0140] III. Representative Embodiments Embodiment 1. A method for providing maintenance therapy to an individual, wherein the maintenance therapy is performed after at least one prior therapy, and comprises administering gemcitabine to the individual two or more consecutive times over two or more delivery periods, the gemcitabine being delivered locally to the individual's bladder, each delivery period being at least one week, with a rest period of at least one month between each delivery period, and the individual having urothelial carcinoma of the lower ureter.

[0141] Embodiment 2. A method of maintenance therapy performed after at least one prior therapy for an individual having urothelial carcinoma of the lower ureter, comprising administering gemcitabine to the individual's bladder two or more times in succession and locally over two or more delivery periods, each delivery period being at least one week, with a rest period of at least one month between each delivery period.

[0142] Embodiment 3. An embodiment according to Embodiment 1 or 2, wherein gemcitabine is delivered into the bladder by an intravesical device.

[0143] Embodiment 4. The method according to Embodiment 3, wherein the intravesical device contains 225 mg of gemcitabine.

[0144] Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the delivery period is 3 weeks each.

[0145] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the rest period is approximately 3 months.

[0146] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein gemcitabine is delivered in a dose of approximately 1 mg / day to approximately 300 mg / day during the delivery period.

[0147] Embodiment 8. The method according to any one of claims 1 to 7, wherein the concentration of gemcitabine in the urine is about 1 μg / mL to about 10 μg / mL during the first and second delivery periods.

[0148] Embodiment 9. The method according to Embodiment 8, wherein the concentration of gemcitabine in the urine is approximately 10 μg / mL during the delivery period.

[0149] Embodiment 10. The method according to any one of Embodiments 1 to 9, wherein the individual is unsuitable for or has rejected cisplatin-based chemotherapy.

[0150] Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein the individual is unsuitable, unqualified, or refuses radical cystectomy.

[0151] Embodiment 12. The method according to any one of Embodiments 1 to 11, wherein the individual has muscle-invasive bladder cancer.

[0152] Embodiment 13. The method according to any one of Embodiments 1 to 11, wherein the individual has nonmuscle-invasive bladder cancer.

[0153] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein the pause period during the delivery period is approximately 3 months.

[0154] Embodiment 15. The method according to any one of Embodiments 1 to 14, comprising four delivery periods, with a rest period of approximately three months between each delivery period.

[0155] Embodiment 16. The method according to any one of Embodiments 1 to 14, wherein the rest period between each delivery period is approximately 3 months, and gemcitabine is delivered every 3 months over the lifespan of the individual.

[0156] Embodiment 17. A method for treating urothelial carcinoma of the lower ureter in an individual, comprising: a) continuously administering an effective dose of gemcitabine to the individual during an induction phase; and b) continuously administering an effective dose of gemcitabine to the individual during a maintenance phase, wherein gemcitabine is delivered locally to the individual's bladder, and the induction and maintenance phases are separated by a rest period, with the induction phase lasting approximately 12 weeks.

[0157] Embodiment 18. A method for treating urothelial carcinoma of the lower ureter in an individual, comprising: a) administering an effective dose of gemcitabine to the individual's bladder continuously and locally during an induction phase of approximately 12 weeks; and b) administering an effective dose of gemcitabine to the individual's bladder continuously and locally during a maintenance phase, wherein the induction and maintenance phases are separated by a rest period.

[0158] Embodiment 19. A method for bladder preservation in an individual, comprising: a) continuously administering an effective dose of gemcitabine to the individual during the induction phase; and b) continuously administering an effective dose of gemcitabine to the individual during the maintenance phase, wherein the gemcitabine is delivered locally to the individual's bladder, the induction phase and the maintenance phase are separated by a rest period, the induction phase is approximately 12 weeks, and the individual has urothelial carcinoma of the lower ureter.

[0159] Embodiment 20. A method for bladder preservation in an individual having urothelial carcinoma of the lower ureter, comprising: a) administering an effective dose of gemcitabine to the individual's bladder continuously and locally during an induction phase of approximately 12 weeks; and b) administering an effective dose of gemcitabine to the individual's bladder continuously and locally during a maintenance phase, wherein the induction phase and the maintenance phase are separated by a rest period.

[0160] Embodiment 21. The method according to any one of Embodiments 17-20, wherein gemcitabine is delivered by an intravesical device.

[0161] Embodiment 22. The method according to Embodiment 21, wherein the intravesical device contains 225 mg of gemcitabine.

[0162] Embodiment 23. The method according to any one of Embodiments 17 to 22, wherein the pause period between the introduction phase and the maintenance phase is approximately 3 months.

[0163] Embodiment 24. The method according to any one of Embodiments 17 to 23, wherein the maintenance period includes two or more gemcitabine delivery periods.

[0164] Embodiment 25. The method according to Embodiment 24, wherein the maintenance gemcitabine delivery period is interrupted by rest periods of approximately 3 months each.

[0165] Embodiment 26. The method according to any one of Embodiments 17 to 25, wherein the maintenance period for gemcitabine delivery is 3 weeks.

[0166] Embodiment 27. The method according to any one of Embodiments 24 to 26, wherein gemcitabine is delivered in a dose of approximately 1 mg / day to approximately 300 mg / day during the induction or maintenance delivery period.

[0167] Embodiment 28. The method according to any one of Embodiments 24 to 27, wherein the concentration of gemcitabine in the urine is approximately 1 μg / mL to approximately 10 μg / mL during the induction or maintenance delivery period.

[0168] Embodiment 29. The method according to any one of Embodiments 17 to 28, wherein the individual is unsuitable for or has rejected cisplatin-based chemotherapy.

[0169] Embodiment 30. The method according to any one of Embodiments 17 to 29, wherein the individual is unsuitable, unqualified, or refuses radical cystectomy.

[0170] Embodiment 31. The method according to any one of Embodiments 17 to 30, wherein the individual has muscle-invasive bladder cancer.

[0171] Embodiment 32. The method according to any one of Embodiments 17 to 30, wherein the individual has nonmuscle-invasive bladder cancer.

[0172] Embodiment 33. The method according to any one of claims 1 to 32, wherein the individual is a human. [Examples]

[0173] (Example 1) On day 0 of the study, subjects received the first TAR-200 transurethraally via a TARIS Inserter. On day 21 (±3 days) of the study, this first TAR-200 was removed via flexible or rigid cystoscopy, and a second TAR-200 was placed. The TAR-200 is an intravesical device containing 225 mg of gemcitabine. This removal / replacement procedure was repeated on days 42 (±3 days) and 63 (±3 days) of the study for the third and fourth administration cycles during the induction phase, respectively. The fourth TAR-200 was removed on day 84 (±3 days) of the study, and a 3-month response evaluation was performed. See Figure 1.

[0174] During the maintenance period, a 21-day administration cycle occurs every quarter (3 months) (starting around month 6). Subjects may continue to receive quarterly administration cycles for three more periods.

[0175] All subjects are evaluated for clinical response by cystoscopy, pelvic computed tomography (CT) / magnetic resonance imaging (MRI) / positron emission tomography (PET), and biopsy (only at week 12 unless clinically indicated) every three months. Subjects are also evaluated for symptom control at weeks 3, 6, 9, and 12, and approximately monthly during the maintenance period.

[0176] The primary endpoint is the assessment of the safety and tolerability of four consecutive 21-day cycles of TAR-200 administration.

[0177] The secondary endpoints are the proportion of subjects with a clinical complete response (cCR), clinical partial response (cPR), stable disease (SD), and progression based on visual lesions on cystoscopy, pelvic CT / MRI / PET, and biopsy. For the purposes of this study, cCR means no signs of disease in the bladder or notes. cPR means, for subjects who were previously N0, downstaging of the bladder tumor burden to <pT2 disease and no signs of nodular disease, and for N1-N3 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of an increase in the size of the nodular disease burden, or no signs of downstaging of the bladder tumor burden and a decrease in the size of the nodular disease burden. Stable disease means persistent MIBC with no signs of metastasis. Progression means M1 disease or a significant increase in the disease burden in the bladder based on cystoscopy and Ct / MRI / PET. Symptom control is defined as the change in bladder-related symptoms according to the protocol-specified bladder symptom and toxicity assessment system. Other secondary endpoints are the time to intervention for symptom control, defined as the time from the date of insertion of the first TAR-200 to the date of intervention for symptom relief, the time to progression, defined as the time from the date of insertion of the first TAR-200 to the date of the first occurrence of progression, the proportion of subjects receiving post-treatment intervention for local symptom management at 3, 6, 9, and 12 months, and the proportion of subjects alive at 12 months.

[0178] To be eligible to participate in this study, subjects must meet all of the following patient eligibility criteria at the time of registration. 1. Histological evidence of muscle-invasive urothelial carcinoma (T2-T4a) of the bladder. Subjects with mixed tissue structures must have a dominant transitional cell pattern. Subjects with evidence of node disease below the aortic bifurcation may also be included (cN0-cN3, M0). 2. The subject must have the tissue removed as completely as possible, according to the doctor's judgment. 3. Subjects must be deemed unsuitable for RC because they have a comorbid condition with a mortality risk, as estimated by the American College of Surgeons risk calculator (http: / / riskcalculator.facs.org / RiskCalculator / PatientInfo.jsp) using physician terminology code 51595 or 51596 for cystectomy, with an RC ≥ 5%. 4. Subjects must refuse cisplatin-based chemotherapy (and understand the risks and benefits of doing so), or be deemed ineligible for cisplatin-based chemotherapy by meeting at least one of the following criteria: World Health Organization (WHO) or Eastern Cooperative Oncology Group (ECOG) general status of ≥2, or Karnofsky general status of 60–70%, creatinine clearance of ≤60 mL / min (calculated or measured), Common Terminology Criteria for Adverse Events (CTCAE) v4 Grade ≥2, hearing loss, peripheral neuropathy of CTCAE v4 Grade ≥2, or New York Heart Association ≥Class III heart failure. 5. A lifespan of at least 4 months. 6. Sufficient bone marrow, liver, and kidney function, as assessed within 21 days prior to administration, by the following requirements: hemoglobin ≥ 7.0 g / dL, absolute neutrophil count (ANC) ≥ 1,500 / mm3, platelet count ≥ 75,000 / mm3, total bilirubin ≤ 2x upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x ULN, and glomerular filtration rate ≥ 30% (≥ 30 mL / min / 1.73 m2). 7. Subjects willingly undergo cystoscopy for the placement and removal of the investigational drug.

[0179] (Example 2) Twenty-three patients were enrolled in the study described in Example 1. The age range of the enrolled patients was 50–98 years. The mean age was 82.6 years, and the median age was 84 years. Patients were treated and evaluated according to the method described herein. Patients who achieved complete response, partial response, or stable disease after the induction phase received maintenance treatment.

[0180] result Seven patients discontinued the study at several points during the induction period for various reasons. Of the remaining 16 patients, 10 completed all four cycles of treatment during the induction period. Five patients completed the 180-day evaluation. The age range of the 16 patients was 50–98. The mean age was 81.75, and the median age was 84.

[0181] At the end of the induction period (day 84 of the study), a complete response rate of 50% and an objective response rate (ORR) of 80% were achieved on a per-protocol basis. See Table 1. On an intention-to-treatment (ITT) basis (including all 23 enrolled patients), a complete response rate of 30% and an objective response rate of 47% were achieved. Four consecutive doses were well tolerated in all 10 patients, and this evidence suggests symptom control and sustained effects at day 180. Eight patients progressed to maintenance therapy.

[0182] [Table 1] NED: No signs of disease.

[0183] The symptoms of hematuria during treatment were evaluated in 13 patients. Four patients had no history of hematuria (such as chronic hematuria, gross hematuria, incidental hematuria, or recurrent gross hematuria) or had only rarely experienced hematuria from day 0. Patients 1 (previously had chronic hematuria), 5 (previously had incidental hematuria), and 9 (previously had recurrent gross hematuria) had no hematuria values ​​from day 0. In particular, patient 1 had no hematuria for 200 days.

[0184] [Table 2] * TBD: Undecided; DC: Cancelled; ND * :Not measured. The inventions described in the original claims of this application are listed below. [Invention 1] A method for providing maintenance therapy to an individual, wherein the maintenance therapy is performed after at least one previous therapy, and the maintenance therapy is: The procedure includes administering gemcitabine to the individual two or more times consecutively during a period of two or more deliveries. The gemcitabine is delivered locally to the bladder of the individual. Each delivery period is at least one week. There is a pause of at least one month between each delivery period. The method wherein the individual has urothelial carcinoma of the lower ureter. [Invention 2] The method according to Invention 1, wherein the gemcitabine is delivered into the bladder by an intravesical device. [Invention 3] The method according to Invention 2, wherein the intravesical device contains approximately 225 mg of gemcitabine. [Invention 4] The method according to any one of inventions 1 to 3, wherein the delivery period is 3 weeks each. [Invention 5] The method according to any one of Inventions 1 to 4, wherein the aforementioned suspension period is approximately 3 years. [Invention 6] The method according to any one of Inventions 1 to 5, wherein gemcitabine is delivered in a dose of approximately 1 mg / day to approximately 300 mg / day during the delivery period. [Invention 7] The method according to any one of Inventions 1 to 6, wherein the concentration of gemcitabine in the urine is approximately 1 μg / mL to approximately 10 μg / mL during the first and second delivery periods. [Invention 8] The method according to Invention 7, wherein the concentration of gemcitabine in the urine is approximately 10 μg / mL during the delivery period. [Invention 9] The method according to any one of Inventions 1 to 8, wherein the individual is unsuitable for or has refused cisplatin-based chemotherapy. [Invention 10] The method according to any one of Inventions 1 to 9, wherein the individual is unsuitable, unqualified, or has refused radical cystectomy. [Invention 11] The method according to any one of inventions 1 to 10, wherein the individual has muscle-invasive bladder cancer. [Invention 12] The method according to any one of inventions 1 to 10, wherein the individual has nonmuscle-invasive bladder cancer. [Invention 13] The method according to any one of Inventions 1 to 12, wherein the pause period during the delivery period is approximately 3 months. [Invention 14] The method according to any one of Inventions 1 to 13, comprising four delivery periods, wherein the pause between each delivery period is approximately three months. [Invention 15] The method according to any one of Inventions 1 to 13, wherein the rest period between each delivery period is approximately 3 months, and the gemcitabine is delivered approximately every 3 months over the lifespan of the individual. [Invention 16] A method for treating urothelial carcinoma of the lower ureter in an individual, a) Continuously administering an effective dose of gemcitabine to the individual during the induction period, b) Continuously administering an effective amount of gemcitabine to the individual during the maintenance phase, The gemcitabine is delivered locally to the bladder of the individual. The aforementioned introduction period and the aforementioned maintenance period are separated by a suspension period. The aforementioned introductory period is approximately 12 weeks, according to the method. [Invention 17] A method of bladder preservation in an individual, a) Continuously administering an effective dose of gemcitabine to the individual during the induction period, b) Continuously administering an effective amount of gemcitabine to the individual during the maintenance phase, The gemcitabine is delivered locally to the bladder of the individual. The aforementioned introduction period and the aforementioned maintenance period are separated by a suspension period. The aforementioned introductory period lasted approximately 12 weeks. The method wherein the individual has urothelial carcinoma of the lower ureter. [Invention 18] The method according to any one of inventions 16 to 17, wherein the gemcitabine is delivered by an intravesical device. [Invention 19] The method according to Invention 18, wherein the intravesical device contains approximately 225 mg of gemcitabine. [Invention 20] The method according to any one of inventions 16 to 19, wherein the pause period between the introduction phase and the maintenance phase is approximately 3 months. [Invention 21] The method according to any one of inventions 15 to 19, wherein the maintenance period includes two or more gemcitabine delivery periods. [Invention 22] The method according to Invention 21, wherein the maintenance gemcitabine delivery period is divided into intervals of approximately 3 months each. [Invention 23] The method according to any one of inventions 16 to 22, wherein the maintenance period for gemcitabine delivery is 3 weeks. [Invention 24] The method according to any one of Inventions 21 to 23, wherein gemcitabine is delivered in a dose of approximately 1 mg / day to approximately 300 mg / day during the induction or maintenance delivery period. [Invention 25] The method according to any one of Inventions 21 to 24, wherein the concentration of gemcitabine in the urine is approximately 1 μg / mL to approximately 10 μg / mL during the induction or maintenance delivery period. [Invention 26] The method according to any one of inventions 16 to 25, wherein the individual is unsuitable for or has refused cisplatin-based chemotherapy. [Discussion 27] The method according to any one of inventions 16 to 26, wherein the individual is unsuitable, unqualified, or has refused radical cystectomy. [Invention 28] The method according to any one of inventions 16 to 27, wherein the individual has muscle-invasive bladder cancer. [Invention 29] The method according to any one of inventions 16 to 27, wherein the individual has nonmuscle-invasive bladder cancer.

Claims

1. A pharmaceutical composition comprising gemcitabine, used to treat muscle-invasive bladder cancer in an individual, wherein the treatment is (a) Gemcitabine is administered sequentially and locally to the individual's bladder during at least four consecutive induction delivery periods, each induction delivery period being approximately 18 to 24 days, and (b) Gemcitabine is administered sequentially and locally to the individual's bladder during each of at least two maintenance delivery periods, each maintenance delivery period being approximately 18 to 24 days, with a rest period of approximately 3 months between the at least two maintenance delivery periods. (a) and (b) are separated by a hiatus of at least approximately three months. The gemcitabine is delivered by an intravesical device. The intravesical device contains approximately 225 mg of gemcitabine. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the resting period separating (a) and (b) is approximately three months.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is delivered in a dose that results in gemcitabine being approximately 1 mg / day to approximately 300 mg / day during each maintenance delivery period.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the concentration of gemcitabine in the urine is about 1 μg / mL to about 10 μg / mL during each maintenance delivery period.

5. The pharmaceutical composition according to claim 4, wherein the concentration of gemcitabine in the urine is approximately 10 μg / mL during each maintenance delivery period.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the individual is unsuitable for or has rejected cisplatin-based chemotherapy.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual is unsuitable for, unqualified for, or has refused radical cystectomy.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the individual has bladder cancer of stage T2, T3, or T4.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the individual has muscle-invasive bladder cancer of type cT2, cT3, T3, or T4a.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the individual has M0 or N0 bladder cancer.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the maintenance period includes four maintenance delivery periods, and the rest period between each maintenance delivery period is approximately three months.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the rest period between each maintenance delivery period is approximately three months, and the pharmaceutical composition is delivered approximately every three months over the lifespan of the individual.

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