WO2024092159A1 - Méthodes de traitement du cancer de la vessie avec de la gemcitabine - Google Patents

Méthodes de traitement du cancer de la vessie avec de la gemcitabine Download PDF

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WO2024092159A1
WO2024092159A1 PCT/US2023/077958 US2023077958W WO2024092159A1 WO 2024092159 A1 WO2024092159 A1 WO 2024092159A1 US 2023077958 W US2023077958 W US 2023077958W WO 2024092159 A1 WO2024092159 A1 WO 2024092159A1
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individual
patients
population
months
treatment
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PCT/US2023/077958
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Christopher CUTIE
Dennis GIESING
John MAFFEO
Melissa Price
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Taris Biomedical Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to methods of treating muscle invasive bladder cancer by administering gemcitabine locally and continuously to the bladder that result in increased overall survival, duration of response, time to progression, progression-rate and/or progression free survival in a population of patients that receive such therapy.
  • Bladder cancer is frequently a disease of the elderly, with a median age at diagnosis of ⁇ 70 years, and represents a substantial public health burden, with approximately 570,000 cases diagnosed annually worldwide. Roughly 25% of incident bladder cancer diagnoses are muscle invasive (MIBC), and approximately 21% of those with high-risk non-muscle invasive bladder cancer will progress to MIBC. Importantly, patients with MIBC have a relatively poor prognosis, with a 5-year overall survival (OS) of 48%-70% with treatment (5% without), and untreated patients are at high risk for near-term, cancer- specific mortality.
  • MIBC muscle invasive
  • OS 5-year overall survival
  • a method of treating muscle invasive bladder cancer in an individual comprising continuously administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein administering such treatment to a population of patients results in an overall survival of at least 12 months in the population of patients; administering such treatment to a population of patients results in a duration of response of at least 12 months in the population of patients; administering such treatment to a population of patients results in a time to progression of at least 12 months in the population of patients; administering such treatment to a population of patients results in a progression- free rate among responders in the population of patients of at least 80% at 6 months; and/or administering such treatment to a population of patients results in a progression-free survival of at least 8 months in the population of patients.
  • the overall survival in the population of patients is about 21 months to about 30 months. In some embodiments, the overall survival in the population of patients is about 27 months. In some embodiments, the overall survival in the population of patients is higher than the overall survival in a group of patients who did not receive curative intent therapy.
  • the duration of response in the population of patients is about 12 months to about 16 months. In some embodiments, the duration of response in the population of patients is about 14 months. [0008] In some embodiments, the time to progression in the population of patients is about 12 months to about 16 months. In some embodiments, the time to progression in the population of patients is about 13.5 months.
  • the progression-free rate among responders in the population of patients is about 80% to about 98% at 6 months. In some embodiments, the progression-free rate among responders in the population of patients is about 92.3% at 6 months. In some embodiments, the progression-free rate among responders in the population of patients is about 60% to about 80% at 12 months. In some embodiments, the progression-free rate among responders in the population of patients is about 70.5% at 12 months.
  • administering such treatment results in a progression-free survival of about 8 months to about 14 months in the population of patients. In some embodiments, administering such treatment results in a progression-free survival of about 13.5 months in the population of patients.
  • the complete response rate in the population of patients is about 20% to about 40%. In some embodiments, the complete response rate in the population of patients is about 31.4%. In some embodiments, a complete response is defined by no evidence of intravesical disease by cystoscopy and biopsy and no evidence of pathological nodal involvement >10 mm.
  • the partial response rate in the population of patients is about 5% to about 10%. In some embodiments, the partial response rate in the population of patients is about 8.6%. In some embodiments, a partial response is defined by downstaged intravesical disease and no evidence of pathologic nodal involvement >10 mm.
  • the rate of stable disease in the population of patients is about 10% to about 30%. In some embodiments, the rate of stable disease in the population of patients is about 17.1%. In some embodiments, stable disease is defined by no change in intravesical disease and no evidence of pathologic nodal involvement >10 mm.
  • the rate of progressive disease in the population of patients is about 10% to about 30%. In some embodiments, the rate of progressive disease in the population of patients is about 17.1%. In some embodiments, progressive disease is defined by no evidence of intravesical disease by cystoscopy and biopsy and evidence of new pathologic nodal disease >10 mm; downstaged intravesical disease and evidence of new pathologic nodal disease >10 mm; increased burden of intravesical disease visually or pathologically and no evidence of pathologic nodal involvement >10 mm; increased burden of intravesical disease visually or pathologically and evidence of new pathological nodal disease >10 mm; or no change in evidence in intravesical disease and evidence of new pathologic nodal disease >10 mm.
  • the time to intervention for the 25th percentile of the population of patients is at least about 3.4 months.
  • the health-related quality of life in the individual is maintained or improved.
  • the health-related quality of life in the population of patients is higher than the health-related quality of life in a group of patients who did not receive curative intent therapy.
  • the health-related quality of life is measured by a FACT-BL score.
  • the FACT-BL score in the population of patients is between about 70 and about 140.
  • the FACT-BL score in the population of patients is about 117.4.
  • the population of patients have cT2-cT3b NO M0 bladder cancer. In some embodiments, the individual has cT2-cT3b NO M0 bladder cancer. In some embodiments, the individual has cT2 bladder cancer. In some embodiments the individual has T2 bladder cancer. In some embodiments, the individual has pT2 bladder cancer.
  • the individual has a mixed histology and/or a documented dominant transitional cell pattern.
  • the individual has a life expectancy of >4 months.
  • the individual has undergone endoscopically visible complete resection via TURBT.
  • the individual receives such treatment within 7 weeks of the TURBT.
  • the individual is deemed unfit for radical by a physician.
  • the individual has a mortality risk of radical cystectomy >3%, as estimated using the American College of Surgeons risk calculator.
  • the individual has refused or was considered medically ineligible for cisplatin-based chemotherapy or radical radiotherapy.
  • the individual is ineligible refuses or is unfit for curative-intent therapy.
  • the individual has not received systemic chemotherapy for urothelial carcinoma of the bladder.
  • the individual has not pelvic radiotherapy ⁇ 6 months before treatment.
  • the individual is elderly and/or frail.
  • the individual is over 80 years old.
  • the individual is male.
  • the individual has a history of tobacco use.
  • the individual has an Eastern Cooperative Oncology Group performance status >3.
  • the individual has a Charlson Comorbidity Index >2.
  • the individual has a prior history of intravesical Bacillus Calmette-Guerin use.
  • the 25th percentile of time to intervention was 3.7 months.
  • the method further comprises assessing the response of the individual to such treatment.
  • assessing the response comprises performing a cystoscopy, a biopsy, and/or imaging.
  • the response is assessed about 3 months after the start of such treatment.
  • the response is assessed more than one year after the start of such treatment.
  • the method further comprises administering about 225 mg of gemcitabine locally to the bladder for about three weeks about every quarter during a maintenance phase.
  • the maintenance phase begins about six months after the start of treatment.
  • the maintenance phase comprises three quarterly maintenance cycles, each comprising delivering gemcitabine continuously to the bladder for about five days to about three weeks.
  • the method further comprises assessing the response to such treatment during the maintenance phase.
  • the individual does not receive a maintenance therapy if the response assessment indicates that the individual has not responded to such treatment.
  • the individual does not have a metastasis.
  • the individual does not have nodal involvement.
  • the gemcitabine is delivered by an intravesical system.
  • the intravesical system comprises about 225 mg gemcitabine.
  • the intravesical system is retained in the bladder through multiple void cycles.
  • the gemcitabine is continuously administered by elution of gemcitabine from gemcitabine HC1 osmotic mini-tablets.
  • the mini- tablets comprises urea as an osmotic agent.
  • the gemcitabine is released by the intravesical system at a rate of about 5 mg/day to about 30 mg/day.
  • administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times comprises inserting an intravesical system comprising about 225 mg gemcitabine into the bladder and removing the intravesical system about three weeks later four times.
  • the concentration of gemcitabine in the urine is about 10 pg/mL to about 25 g/mL during the administration.
  • the concentration of gemcitabine in the urine is about 18.5 pg/mL during the administration.
  • the concentration of 2',2'-difluorodeoxyuridine (dFdU) in the urine is about 1 pg/mL to about 10 pg/mL during the administration.
  • the concentration of dFdU in the urine is about 6.7 pg/mL during the administration.
  • gemcitabine is undetectable in the plasma of the individual during the administration.
  • the concentration of 2',2'-difluorodeoxyuridine (dFdU) in the plasma is less than 0.5 pg/mL.
  • the gemcitabine is delivered during a portion of a three week administration period.
  • the gemcitabine is delivered for a period of about 5 days to about 14 days.
  • kits comprising an intravesical system comprising about 225 mg gemcitabine and instructions for use according to any one of the methods described herein.
  • an article of manufacture comprising an intravesical system comprising about 225 mg gemcitabine and a package insert comprising instructions for us according to any one of methods described herein.
  • FIG. 1 depicts the design of the TAR-200-103 study. Patients received 4 consecutive 21- day cycles of TAR-200 during an 84-day induction period. Patients underwent efficacy assessments at day 84. Cytology, cystoscopy, and imaging were performed every 3 months during the optional maintenance period, which consisted of additional 21 -day cycles every three months for up to 3 cycles.
  • FIG. 2 shows the distribution of enrolled patients. Each box indicates a status and the number of patients.
  • FIG. 3A shows the Kaplan-Meier estimate of overall survival.
  • FIG. 3B shows the Kaplan-Meier estimate of progression-free survival.
  • FIG. 4 is a swimmer plot of tumor responses. Study day is indicated on the x-axis; individual patients are plotted along the y-axis, with the event or status of each patient indicated according to the legend in the lower right portion of the graph.
  • the administration schedule of the TAR-200 intravesical drug delivery systems is depicted above the swimmer plot.
  • the four overlapping “TAR-200” boxes represent the 4 consecutive 21 -day cycles of TAR-200 administration during the 84-day induction period.
  • the three “TAR-200” boxes on Day 180, Day 270, and Day 365 represent the 3 additional quarterly maintenance cycles of TAR-200.
  • FIG. 5 shows a gemcitabine delivery system, TAR-200.
  • TAR-200 is an intravesical drug delivery system consisting of two components: (i) the drug constituent, which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent; and (ii) the device constituent, which is comprised of a dual lumen silicone part with a single laser-machined orifice and a superelastic nitinol wire (“wireform”). The large lumen of the silicone part contains the gemcitabine and urea minitablets and serves as an elementary osmotic pump to release drug in a controlled manner.
  • the drug constituent which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent
  • device constituent which is comprised of a dual lumen silicone part with a single laser-machined orifice
  • the smaller lumen contains the nitinol wire in a predefined form to provide retention of the system in the bladder during the indwelling period.
  • TAR-200 is shown in an exemplary retention shape (e.g., in a so-called “pretzel shape”) suited to retain the device within the bladder.
  • the retention shape provides, among other things, that the device resists becoming entrained in urine and excreted when the individual voids.
  • FIG. 6 shows TAR-200 in the relatively straightened shape suited for insertion through the urethra of a patient (“deployment shape,” center and right panels in the top row, left and center panels in the bottom row) and into the patient's bladder and a retention shape suited to retain the device within the bladder (top left and bottom right panels).
  • FIG. 7 depicts the design of the TAR-200-103 study. Patients received 4 consecutive 21- day cycles of TAR-200 during an 84-day induction period. Patients underwent efficacy assessments at day 84. Cytology, cystoscopy, and imaging were performed every 3 months during the optional maintenance period, which consisted of additional 21 -day cycles every three months for up to 3 cycles. Also shown are the timings of efficacy analyses including cystoscopy, CT/MRI/PET imaging, biopsy, bladder symptoms, and the Functional Assessment of Cancer Therapy - Bladder Cancer (FACT-BL).
  • FACT-BL Functional Assessment of Cancer Therapy - Bladder Cancer
  • FIG. 8 shows the Kaplan-Meier Plot of duration of response.
  • FIG. 9 shows the Kaplan-Meier analysis of time to intervention.
  • FIG. 10 shows the Kaplan-Meier Plot of time to progression.
  • FIG. 11 shows the Kaplan-Meier Plot of progression-free survival.
  • FIG. 12 shows the Kaplan-Meier Plot of overall survival.
  • kits for treating muscle invasive bladder cancer comprising administering gemcitabine locally to the bladder for a prolonged period. For example, by administering gemcitabine over a 21 -day dosing cycle four consecutive times without a rest period, for a total of about 84 days.
  • the present methods have significant advantages for treatment of muscle invasive bladder cancer, as described herein. For example, in some embodiments, the present methods result in increased overall survival, duration of response, time to progression, progression-rate and/or progression free survival in a population of patients that receive such therapy. In some embodiments, improvement of any of the endpoints is statistically significantly improved following such treatment.
  • any of the endpoints are improved in the population patients that has received such therapy as compared to patients who have not received curative intent therapy.
  • the methods provided herein can be used to increase longevity and decrease mortality in patients who are not eligible for curative intent therapy. For example, patients who are elderly or too frail to receive systemic chemotherapy and/or those who are unwilling and/or unable to undergo radical cystectomy (removal of the bladder). Prior to the present invention, such patients had limited treatment options and a relatively poor prognosis.
  • the present methods are used in conjunction with surveillance and/or maintenance therapy after an initial induction phase.
  • administering refers to providing a therapeutic agent to an individual.
  • a particular amount of drug is administered to the individual, and only a portion of the drug is delivered (or released).
  • an administration period is a period during which a device comprising a drug, such as gemcitabine, remains in the individual’s bladder, also referred to as the indwelling period.
  • the administration period when a device remains in the individual’s bladder is longer than a delivery period of the drug.
  • Delivery is used herein to refer to release of a drug.
  • a delivery period is a period during which an effective amount of a drug, such as gemcitabine, is released from, for example, an intravesical device.
  • the delivery period may comprise only a portion of an administration period.
  • the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For example, “a” or “an” means “at least one” or “one or more.”
  • continuous or “continuously” as used herein refers to sustained administration of a therapeutic agent (such as gemcitabine) over a sustained period of time.
  • a therapeutic agent such as gemcitabine
  • the term "individual” as used herein refers to a human.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), suppressing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing or improving the quality of life, increasing weight gain, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual.
  • the method comprises administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks, four times.
  • the methods provided herein comprise continuous delivery or release of gemcitabine during at least a portion of the administration period.
  • gemcitabine is continuously delivered into the bladder during the administration period.
  • gemcitabine is continuously delivered to the bladder for at least about 24 hours (such as at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, or up to 21 days).
  • gemcitabine is administered to the bladder for 21 days.
  • the delivery period of the drug is shorter than the administration period, e.g., the administration period in which the device comprising gemcitabine remains in the individual’s bladder for 21-days, and the delivery period in which the drug is released from the device is about 7 days.
  • the administration period is 21 days and 225 mg gemcitabine is delivered for 7 days.
  • the administration period is 21 days and 225 mg gemcitabine is delivered for 14 days.
  • the administration period is 21 days and 225 mg gemcitabine is delivered for 21 days.
  • gemcitabine is delivered at a dose of from about 1 mg/day to about 225 mg/day, such as any of about 1 mg/day to about 5 mg/day, about 5 mg/day to about 10 mg/day, about 10 mg/day to about 50 mg/day, about 20 mg/day to about 50 mg/day, about 20 mg/day to about 40 mg/day, about 50 mg/day to about 100 mg/day, about 100 mg/day to about 225 mg/day, about 200 mg/day to about 225 mg/day.
  • the gemcitabine is delivered at a dose of about 1 mg/day to about 45 mg/day.
  • the gemcitabine is delivered at a dose of about 5 mg/day to about 30 mg/day.
  • about 100 mg to about 225 mg of gemcitabine is delivered to the individual. In some embodiments, about 160 mg of gemcitabine is delivered to the individual over seven days. In some embodiments, about 100 mg to about 225 mg of gemcitabine is delivered to the individual over seven days. In some embodiments, about 200 mg to about 225 mg of gemcitabine is delivered to the individual over 21 days. In some embodiments, about 70% of the total gemcitabine is delivered to the individual in the first 7 days. In some embodiments, about 90% of the total gemcitabine is delivered to the individual by day 21.
  • about 225 mg of gemcitabine is delivered to the individual over 7 days. In some embodiments, about 225 mg of gemcitabine is delivered to the individual over 14 days. In some embodiments, about 225 mg of gemcitabine is administered to the individual over 21 days.
  • the concentration of gemcitabine in the urine during administration is about 10 pg/mL to about 20 pg/mL, such as about any of about 10-12, about 12-14, about 14-16, about 16-18, or about 18-20 g/mL. In some embodiments, the concentration of gemcitabine in the urine is about 18.5 g/mL during the administration period.
  • the concentration of 2',2'-difluorodeoxyuridine (dFdU) in the urine is about 1 pg/mL to about 10 pg/mL during the administration period and/or the delivery period. In some embodiments, the concentration of dFdU in the urine is about 1 to about 2, about 2 to about 3, about 3 to about 4, about 4 to about 5, about 5 to about 6, about 6 to about 7, about 7 to about 8, about 8 to about 9, or about 9 to about 10 pg/mL during the administration period and/or the delivery period. In some embodiments, the concentration of dFdU in the urine is about 6.7 pg/mL during the administration period and/or the delivery period.
  • gemcitabine concentration in the plasma of the individual is less than about 1 pg/mL, such as less than about any of 0.5, 04, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 pg/mL.
  • gemcitabine is undetectable in the plasma of the individual during the administration.
  • upon delivery of gemcitabine the ratio of gemcitabine in the urine to gemcitabine in the plasma of the individual is greater than about 500:1.
  • the plasma concentration of dFdU is less than 0.5 pg/mL upon delivery of gemcitabine.
  • the plasma concentration of dFdU is less than 0.2 pg/mL upon delivery of gemcitabine. In some embodiments the plasma concentration of dFdU is less than 0.1
  • the method comprises two or more administration periods that are not separated by a rest period. In some embodiments, the method comprises four administration periods. In some of these embodiments, the administration periods are each about three weeks.
  • gemcitabine is administered to the bladder for 21 days.
  • gemcitabine is continuously delivered into the bladder during the 21 day administration period, or a portion thereof.
  • the gemcitabine is delivered to the bladder for at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, or at least about 21 days.
  • gemcitabine is delivered to the bladder over a period of about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 7 days to about 14 days, about 7 days to about 21 days, about 14 days to about 21 days.
  • gemcitabine is continuously delivered into the urine in the bladder.
  • gemcitabine is administered locally to the bladder of an individual for 21 days.
  • an effective amount of gemcitabine is delivered during the 21 day administration period, or a portion thereof.
  • the gemcitabine may be delivered at a dose of about 1 mg/day to about 225 mg/day.
  • gemcitabine is delivered at a dose of about 5 mg/day to about 225 mg/day, about 10 mg/day to about 225 mg/day, about 15 mg/day to about 100 mg/day, about 15 mg/day to about 50 mg/day, about 5 mg/day to about 50 mg/day, about 5 mg/day to about 40 mg/day, about 5 mg/day to about 30 mg/day, or about 20 mg/day to about 40 mg/day.
  • gemcitabine is delivered at a dose of about 1 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 23 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 200 mg/day, or about 225 mg/day.
  • the total amount of gemcitabine delivered to the individual during an administration period may range from about 50 mg to about 225 mg, from about 75 mg to about 225 mg, from about 100 mg to about 225 mg, from about 200 mg to about 225 mg, or from about 100 mg to about 225 mg. In some embodiments about 225 mg of gemcitabine is administered to the individual. In some embodiments, about 100 to about 225 mg of gemcitabine (e.g., about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, or about 225 mg) of gemcitabine is administered to the individual over seven days.
  • about 100 to about 225 mg of gemcitabine e.g., about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, or about 225 mg
  • about 225 mg of gemcitabine is administered to an individual for three weeks.
  • the concentration of gemcitabine in the urine is from about 10
  • gemcitabine is administered locally to the bladder, upon delivery of gemcitabine, the concentration of gemcitabine present in the urine of the individual is higher than the plasma, which may be beneficial for reducing side effects of gemcitabine.
  • local delivery of gemcitabine to the bladder may result in decreased neutropenia, lymphedema, anemia, thrombocytopenia, fatigue, pain, hair loss, reproductive dysfunction, or memory impairment caused by systemic chemotherapy.
  • the ratio of concentration of gemcitabine in the urine of the individual to the concentration of gemcitabine in the plasma of the individual is greater than about 100:1, greater than about 200: 1, greater than about 300: 1, greater than about 400: 1, greater than about 500:1, greater than about 600:1, greater than about 700: 1, or greater than about 1000: 1.
  • gemcitabine is undetectable in the plasma of the individual during administration.
  • gemcitabine is administered locally to the bladder in four consecutive 21 -day cycles.
  • the methods herein comprise (i) placing a first gemcitabine releasing intravesical system into the bladder of the individual on day 0, (ii) removing the first gemcitabine releasing intravesical system on about day 21, (iii) placing a second gemcitabine releasing intravesical system in the bladder of the individual at about day 21, (iv) removing the second gemcitabine releasing intravesical system at about day 42, (v) placing a third gemcitabine releasing intravesical system in the bladder of the individual at about day 42, (vi) removing the third gemcitabine releasing intravesical system at about day 63, (vii) placing a fourth gemcitabine releasing intravesical system in the bladder of the individual at about day 63, and (viii) removing the fourth gemcitabine releasing intravesical system at about day 84.
  • up to an additional three 21 day cycles comprising gemcitabine releasing intr
  • a method of treating muscle invasive bladder cancer in an individual comprising administering gemcitabine locally to the bladder of the individual for about three weeks, four times.
  • a method of treating muscle invasive bladder cancer in an individual comprising administering gemcitabine locally and continuously to the bladder of the individual for about three weeks, four times.
  • a method of treating muscle invasive bladder cancer in an individual comprising administering gemcitabine locally and continuously to the bladder of the individual for about three weeks, four times, wherein the gemcitabine is administered by an intravesical system.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual comprising (i) placing a gemcitabine releasing intravesical system into the bladder of the individual, wherein the intravesical system remains in the bladder for about three weeks and wherein the gemcitabine is continuously delivered to the bladder.
  • a method of treating muscle invasive bladder cancer in an individual comprising (i) placing a gemcitabine releasing intravesical system into the bladder of the individual, wherein the system remains in the bladder for about three weeks and wherein the gemcitabine releasing intravesical system delivers gemcitabine passively.
  • a method of treating muscle invasive bladder cancer in an individual comprising (i) placing a first gemcitabine releasing intravesical system into the bladder of the individual on day 0, (ii) removing the first gemcitabine releasing intravesical system on about day 21, (iii) placing a second gemcitabine releasing intravesical system in the bladder of the individual at about day 21, (iv) removing the second gemcitabine releasing intravesical system at about day 42, (v) placing a third gemcitabine releasing intravesical system in the bladder of the individual at about day 42, (vi) removing the third gemcitabine releasing intravesical system at about day 63, and (vii) placing a fourth gemcitabine releasing intravesical system in the bladder of the individual at about day 63, (viii) removing the fourth gemcitabine releasing intravesical system at about day 84.
  • up to an additional three 21 day cycles comprising gemcitabine releasing intravesical systems are placed into the bladder of the individual starting at day 180.
  • one additional 21 -day cycle comprising a gemcitabine releasing intravesical system is placed into the bladder of the individual starting at day 180.
  • two additional 21 -day cycles comprising gemcitabine releasing intravesical systems are placed into the bladder of the individual starting at day 180.
  • three 21 day cycles comprising gemcitabine releasing intravesical systems are placed into the bladder of the individual starting at day 180
  • the intravesical system contains 225 mg of gemcitabine before placement into the bladder.
  • the method further comprises assessing the response of the individual to the treatment.
  • assessing the response comprises performing a cystoscopy, a biopsy, and/or imaging.
  • the response is assessed about 3 months after the start of such treatment (e.g., after the fourth three-week gemcitabine administration period). In some embodiments, the response is assessed about 84 days after the start of such treatment. In some embodiments, the response is assessed by cystoscopy of visible lesions, chest/abdominal/pelvic imaging (computed tomography, magnetic resonance imaging, or positron emission tomography), and pathological staging of the bladder biopsy.
  • the method further comprises administering about 225 mg of gemcitabine locally to the bladder for about three weeks about every quarter during a maintenance phase.
  • the maintenance phase begins about 3 months after the start of treatment.
  • the maintenance phase comprises three quarterly maintenance cycles, each comprising delivering gemcitabine continuously to the bladder for about three weeks, or a portion of a three week delivery period.
  • the method further comprises assessing the response to such treatment during the maintenance phase.
  • the maintenance phase begins about 180 days after the start of treatment with gemcitabine.
  • the individual does not receive a maintenance therapy if the response assessment indicates that the individual has not responded to such treatment.
  • the response assessment comprises cystoscopy of visible lesions, chest/abdominal/pelvic imaging (computed tomography, magnetic resonance imaging, or positron emission tomography), and pathological staging of the bladder biopsy.
  • bladder cancer is carcinoma in situ.
  • the bladder cancer is BCG (Bacillus Calmette-Guerin) refractory cancer.
  • the bladder cancer is papillary bladder cancer.
  • the bladder cancer is grade 1/3, 2/3, or 3/3.
  • the bladder cancer is stage I, stage II, stage III, or stage IV bladder cancer.
  • the bladder cancer is high grade invasive papillary urothelial carcinoma.
  • the bladder cancer is non-invasive high grade urothelial carcinoma.
  • the bladder cancer is multifocal invasive high grade papillary urothelial carcinoma.
  • the bladder cancer is T2 or T3.
  • the bladder cancer is staged clinically, such as using a biopsy or imagining.
  • the bladder cancer is clinical stage cT2 or cT3.
  • the bladder cancer is clinical stage cT2 with carcinoma in situ.
  • the bladder cancer is staged pathologically, after bladder removal.
  • the bladder cancer is pathological stage pT2 or pT3.
  • the tumor has invaded the muscularis propria.
  • the tumor has invaded the superficial muscularis basement.
  • the tumor has invaded the deep muscularis basement.
  • the tumor has invaded perivesical tissue.
  • the tumor has invaded the perivesical tissue microscopically. In some embodiments, the tumor has invaded the perivesical tissue macroscopically. In some embodiments, the individual does not have a distant metastasis (MO). In some embodiments, the individual does not have a lymph node metastasis (NO) In some embodiments, the bladder cancer stage is determined using the NCCN guidelines, which are hereby incorporated by reference.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual who is not eligible for neoadjuvant cisplatin-based therapy comprising administering gemcitabine locally to the bladder.
  • a method of treating muscle invasive bladder cancer in an individual who refuses or is considered medically-ineligible for neoadjuvant cisplatin-based therapy comprising administering a gemcitabine locally to the bladder.
  • provided herein is a method of treating muscle-invasive bladder cancer in an individual having cT2 disease.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual having T2 disease.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual having pT2 disease.
  • the individual has T2 disease and does not progress to T3 disease.
  • the individual has cT2 cancer.
  • the individual has an organ-confined muscle invasive bladder cancer (such as non-metastatic MIBC (i.e., MO MIBC), such as MO NO MIBC).
  • MO MIBC non-metastatic MIBC
  • the individual has a cT2 MO NO MIBC.
  • the individual has T2 MIBC such as cT2 or pT2 MIBC.
  • the individual has T2 MIBC such as pT2a or pT2b MIBC.
  • individual is ineligible, refuses, or is unfit for curative-intent therapy.
  • the individual has not received systemic chemotherapy for urothelial carcinoma of the bladder.
  • the individual has not received pelvic radiotherapy ⁇ 6 months before treatment.
  • an individual is ineligible for cisplatin-based therapy based upon co-morbidities including poor performance status, poor renal function, hearing loss, peripheral neuropathy, and cardiac disease.
  • an individual is ineligible for cisplatin-based therapy based upon the absence of one or more high-risk features such as lymphovascular invasion (LVI), hydronephrosis, and concomitant carcinoma in situ (CIS).
  • LMI lymphovascular invasion
  • CIS concomitant carcinoma in situ
  • the present invention provides a method of treating muscle invasive bladder cancer in an individual who is unfit or not eligible for a cystectomy by administering gemcitabine locally to the bladder.
  • provided herein is a method of treating muscle invasive bladder cancer of the lower tract in an individual who is unfit for cystectomy comprising delivering gemcitabine locally to the bladder. In some embodiments, provided herein is a method of treating muscle-invasive bladder cancer in an individual who is ineligible for cystectomy comprising delivering gemcitabine locally to the bladder. In some embodiments, provided herein is a method of treating muscle invasive bladder cancer in an individual who is frail comprising delivering gemcitabine locally to the bladder. In some embodiments, provided herein is a method of treating muscle invasive bladder cancer in an individual who cannot tolerate radical cystectomy comprising delivering gemcitabine locally to the bladder.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual without removing the bladder of the individual, comprising delivering gemcitabine locally to the bladder. In some embodiments, provided herein is a method of treating muscle invasive bladder cancer in an individual, wherein the individual is unfit or ineligible for a cystectomy, comprising delivering gemcitabine locally to the bladder. In some embodiments, provided herein is a method of treating muscle invasive bladder cancer in an individual, wherein the bladder cancer is metastatic bladder cancer.
  • provided herein is a method of treating bladder cancers, (for example MIBC) in an individual, wherein the individual has cT2-cT3 disease (such as cT2-cT3 MO disease), comprising delivering gemcitabine locally to the bladder.
  • cT2-cT3 disease such as cT2-cT3 MO disease
  • a method of treating cT2 muscle invasive bladder cancer in an individual who is ineligible for cystectomy comprising delivering gemcitabine locally to the bladder.
  • a method of treating T2 muscle invasive bladder cancer in an individual comprising delivering gemcitabine locally to the bladder of the individual, wherein the bladder cancer does not progress to T3.
  • provided herein is a method of treating T2 muscle invasive bladder cancer in an individual who is unfit or ineligible for radical cystectomy comprising delivering gemcitabine locally to the bladder of the individual, wherein the bladder cancer does not progress to T3.
  • a method of treating T2 muscle invasive bladder cancer in an individual who cannot tolerate radical cystectomy comprising delivering gemcitabine locally to the bladder, wherein the bladder cancer does not progress to T3.
  • provided herein is a method of treating T2 muscle invasive bladder cancer in an individual who is not eligible for neoadjuvant cisplatin-based therapy comprising administering gemcitabine locally to the bladder, wherein the bladder cancer does not progress to T3.
  • a method of treating T2 muscle invasive bladder cancer in an individual who refuses or is considered medically-ineligible for neoadjuvant cisplatin-based therapy comprising administering a gemcitabine locally to the bladder, wherein the bladder cancer does not progress to T3.
  • the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is unfit for, ineligible for or has refused a radical cystectomy. [0109] In some embodiments, the individual is ineligible for radical cystectomy under the National Comprehensive Cancer Network (NCCN) guidelines. For example, the individual may be unfit for curative therapy due to frailty. Prior to the present methods, such individuals typically received palliative radiation without chemotherapy (3.5 Gy/fraction - 10 treatments; or 7Gy/fraction - 7 treatments; TURBT; or no treatment). In some embodiments the individual is unfit for platinum-based chemotherapy. In some embodiments, chemotherapy prior to radiation therapy is not recommended for the individual. In some embodiments, the individual does not receive curative therapy or systemic chemotherapy. In some embodiments, the individual has cT2-cT3 disease (such as cT2-cT3 MO disease). In some embodiments, the individual is elderly and/or frail.
  • NCCN National Comprehensive Cancer Network
  • the individual cannot tolerate radical cystectomy based upon the American Society of Anesthesiology (ASA) guidelines.
  • ASA American Society of Anesthesiology
  • the individual who cannot tolerate radial cystectomy may be deemed medically unfit for surgery requiring general or epidural anesthesia.
  • the individual has a mortality risk of radical cystectomy >3%, as estimated using the American College of Surgeons risk calculator.
  • the bladder cancer is resected prior to administration of the gemcitabine.
  • the individual undergoes a TURBT prior to administration of the gemcitabine to the bladder.
  • the individual receives administration of gemcitabine within 7 weeks of the TURBT.
  • the tumor is maximally resected prior to administration of the gemcitabine such that no visible tumor is present.
  • the tumor is non-maximally resected prior to administration of the gemcitabine.
  • the tumor is non- maximally resected prior to administration of the gemcitabine such that residual tumor is present.
  • the patient is TO after TURBT.
  • the individual has undergone TURBT and has residual tumor at the site of resection, wherein the amount of residual tumor is sufficient to provide a tumor antigen to elicit an immune response.
  • about ⁇ i, 1/3, *4, 1/5, 1/6, 1/7, 1/8, 1/9, 1/10, 1/20, 1/50, 1/100 of the original tumor amount remains after TURBT.
  • at least Yi, 1/3, Vi, 1/5, 1/6, 1/7, 1/8, 1/9, 1/10, 1/20, 1/50, 1/100 of the original tumor amount remains after TURBT.
  • the individual has stage Ta, Tis, Tl, T2, T2a, T2b, T3, T3a, T4, T4a, or T4b cancer following TURBT.
  • the individual may lack operative post-operative care infrastructure or personal as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists. Under these guidelines, an individual is deemed frail if he or she shows abnormal independent activities of daily living, severe malnutrition, cognitive impairment, or comorbidities cumulative illness rating scale for geriatrics (CISR-G) grades 3-4.
  • CISR-G geriatrics
  • the methods of the present invention also provide important and significant treatment benefits compared to standard therapeutic regimens that call for removal of the bladder.
  • the present invention also has the advantage of being useful as a bladder sparing protocol for individuals who are eligible for a cystectomy, but elect not to have a cystectomy.
  • the present methods result in a greatly improved quality of life for individuals, who may be able to retain their bladder after having bladder cancer, compared to the presently available treatments.
  • a bladder sparing method of treating muscle invasive bladder cancer in an individual comprising delivering a gemcitabine locally to the bladder.
  • a method of treating muscle invasive bladder cancer without removing the bladder of the individual comprising delivering gemcitabine) locally to the bladder in some embodiments, provided herein is a method of preserving the bladder of an individual, comprising delivering gemcitabine locally to the bladder.
  • provided herein is a method of preserving the bladder of an individual with cT2 bladder cancer.
  • the present methods are especially suited for treatment of cT2 patients who would typically receive a radical resection followed by neoadjuvant therapy.
  • the present methods result in local/regional (locoregional) control of the disease, including nodes, and thus can be used for long-term treatment in this bladder sparing population, in some embodiments, the present methods also result in freedom from invasive recurrence, good long term bladder function, and low rates of salvage cystectomy, all of which are of major importance in the elderly, relatively frail population of individuals with bladder cancer who have an average age of 70.
  • the individual has muscle invasive bladder cancer (MIBC).
  • MIBC muscle invasive bladder cancer
  • the individual has non-metastatic (MO) bladder cancer (e.g., MIBC).
  • the individual has NO bladder cancer (e.g., MIBC).
  • the individual has Nl, N2, or N3 bladder cancer (e.g., MIBC).
  • the individual has cT2 bladder tumor or cT3 bladder tumor (e.g., MIBC).
  • the individual has Ta, Tis, Tl, T2 (e.g., T2a and/or T2b), T3 (e.g., T3a and/or T3b), T4 (e.g., T4a and/or T4b) bladder cancer (e.g., MIBC).
  • the individual has NO and MO bladder cancer (e.g., MIBC). In some embodiments, the individual has cT2-cT3b NO MO bladder cancer. In some embodiments, the individual has cT2, NO, MO MIBC. In some embodiments, the individual has cT3, NO, MO MIBC.
  • MO bladder cancer e.g., MIBC
  • the individual has cT2-cT3b NO MO bladder cancer. In some embodiments, the individual has cT2, NO, MO MIBC. In some embodiments, the individual has cT3, NO, MO MIBC.
  • the population of patients have cT2-cT3b NO MO bladder cancer. In some embodiments, the population of patients have T2, such as cT2 or pT2 bladder cancer.
  • the individual has a prior history of intravesical Bacillus Calmette-Guerin (BCG) therapy. In some embodiments, the individual is BCG-unresponsive after treatment with adequate BCG therapy.
  • BCG Bacillus Calmette-Guerin
  • the individual is elderly and/or frail. In some embodiments, the individual is at least about 60, 65, 70, 75, 80, 85 or 90 years old. In some embodiments, the individual is over 80 years old. In some embodiments, the individual has a compromised immune system.
  • the individual is male.
  • the individual has a history of tobacco use.
  • the individual has an Eastern Cooperative Oncology Group performance status >3.
  • the Eastern Cooperative Oncology Group performance status scale is a standard criteria for measuring how disease impacts a patient’s daily living abilities, referred to as a patient’s performance status.
  • the status scale provides a way to define the population of patients in the trial, guide enrollment into studies, and track changes in a patient’s level of functioning as a result of treatment during the trial. See, e.g., Oken et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group, Am J Clin Oncol. 1982 Dec;5(6):649-55, which is hereby incorporated by reference in its entirety.
  • the individual has a Charlson Comorbidity Index >2.
  • the Charlson Comorbidity index predicts one-year mortality in patients with multiple comorbidities. Each condition is assigned a score depending on the risk of dying associated with each risk. See, e.g., Charlson et al., A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation, J. of Chronic Diseases 1987 40 (5): 373-83, which is hereby incorporated by reference in its entirety.
  • the individual does not have a metastasis. In some embodiments, the individual does not have nodal involvement.
  • the 25th percentile of time to intervention is between about 2 months and about 5 months. In some embodiments, the 25th percentile of time to intervention is about 3.7 months.
  • kits for treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein administering such treatment to a population of patients results in an overall survival of at least 12 months in the population of patients; administering such treatment to a population of patients results in a duration of response of at least 12 months in the population of patients; administering such treatment to a population of patients results in a time to progression of at least 12 months in the population of patients; administering such treatment to a population of patients results in a progression- free rate among responders in the population of patients of at least 80% at 6 months; and/or administering such treatment to a population of patients results in a progression-free survival of at least 8 months in the population of patients.
  • provided here are methods of treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times that result in an increase in overall survival (OS) in a population of patients who have received such treatment.
  • OS describes the time from the date of the first insertion of TAR-200 to the date of the first occurrence of progression of disease or death, or censoring at the date of last evaluable disease assessment.
  • the present methods beneficially result in longer OS than patients who did not receive or were ineligible for curative-intent therapy.
  • the individual experiences a longer lifespan following treatment than he or she would have otherwise.
  • the treatments provided herein reduce mortality in individuals having muscle invasive bladder cancer.
  • the prognosis for patients with muscle invasive bladder cancer is improved.
  • the overall survival is increased in comparison to the standard of care for muscle invasive bladder cancer.
  • the overall survival is increased in comparison to overall survival in a group of patients who have not received curative intent therapy.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • the overall survival compares favorably to the overall survival of individuals with MIBC who did not receive or were ineligible for curative intent therapy.
  • the methods provided herein result in a statically significant increase in overall survival in the population of patients having received local administration of gemcitabine to the bladder.
  • the overall survival of the population of patients is at least 12 months.
  • the overall survival of the population of patients is at least 21 months.
  • the overall survival in the populations of patients is about 21 months to about 30 months.
  • the overall survival in the population of patients is about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30 or about 31 months.
  • the overall survival in the population of patients is about 27 months.
  • the overall survival in the population of patients is about 27.3 months.
  • the overall survival in the population of patients is about 2.3 months with a 95% confidence interval. In some embodiments, the overall survival is determined using a Kaplan-Meier estimate. In some embodiments, the overall survival is increased in comparison to overall survival in a group of patients who have not received curative intent therapy. In some embodiments, the individual and/or population of patients is unfit or ineligible for curative intent therapy. In some embodiments, the individual and/or population of patients is elderly or frail.
  • the methods provided herein result in an increased duration of response (DOR) in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • duration of response is defined as the time from first observation of CR or PR to the first observation of progressive disease or death in patients that had a response.
  • the increased duration of response allows the individual to receive fewer rounds and less chemotherapy overall and enables the individual to be treated in a maintenance therapy regimen and/or for the individual to undergo periodic (such as quarterly) surveillance.
  • the duration of response is increased in a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the duration of response is increased compared to a group of patients who did not receive curative intent therapy.
  • the duration of response in the population of patients is at least 10 months. In some embodiments the duration of response in the population of patients is at least 13 months, or at least 14 months. In some embodiments, the duration of response is about 10 months to about 23 months, about 10 months to about 20 months, about 12 months to about 16 months, about 12 months to about 15 months, about 12 months to about 14 months, or about 14 months to about 16 months. In some embodiments, the duration of response is about 12, about 13, about 14, about 15, or about 16 months. In some embodiments, the duration of response is about 14 months. In some embodiments, the median duration of response is about 14 months. In some embodiments, the duration of response within an 95% confidence interval is about 14 months.
  • the duration of response is determined by a Kaplan-Meier plot.
  • the methods provided herein result in an increased time to progression in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • time to progression is calculated as the time from the date of the first insertion of TAR-200 to the date of the first occurrence of PD or censoring at the time of last evaluable disease assessment.
  • disease progression comprises an upstaging in the tumor.
  • the increased time to progression is statistically significant.
  • the time to progression is increased in a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the time to progression is increased compared to a group of patients who did not receive curative intent therapy.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • the time to progression for individuals receiving such treatment is at least 12 months, at least 13 months, at least 14, months, at least 15 months, or at least 16 months. In some embodiments the time to progression is about 12 months to about 16 months, about 12 months to about 15 months, about 12 months to about 14 months, or about 14 months to about 16 months. In some embodiments, the time to progression is about 12, about 13, about 14, about 15, or about 16 months. In some embodiments, the time to progression is about 13.5 months.
  • the methods provided herein result in an increased progression- free rate in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • the progression- free rate is expressed as the percentage of patients still in response at 6 and 12 months.
  • the increased progression-free rate is statistically significant.
  • the progression-free rate is increased a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the progression-free rate is increased compared to a group of patients who did not receive curative intent therapy.
  • the progression- free rate is the progression-free rate of “responders” i.e.
  • a responder is an individual who did not show disease progression within a particular time frame.
  • the progression-free rate is the progression-free rate 6 months after treatment.
  • the progression-free rate is the progression-free rate 12 months after treatment.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • the methods provided herein result in an increased progression- free rate of responders in a population of patients with muscle invasive bladder cancer of at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% at 6 months.
  • the progression-free rate of responders at 6 months is about 80% to about 98%, about 85% to about 95%, or about 88% to about 93%.
  • the progression-free rate of responders at 6 months is about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%.
  • the progression-free rate of responders at 6 months is about 92.3%.
  • the methods provided herein result in an increased progression- free rate of responders in a population of patients with muscle invasive bladder cancer of at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% at 12 months.
  • the progression-free rate of responders at 12 months is about 60% to about 80%, about 65% to about 80%, or about 65% to about 75%.
  • the progression-free rate of responders at 6 months is about 68%, about 69%, about 70%, about 71%, about 72%, or about 73%.
  • the progression-free rate of responders at 12 months is about 70.5%.
  • the methods provided herein result in an increased progression- free survival in in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • progression-free survival is defined as the time from the date of the first insertion of TAR- 200 to the date of the first occurrence of progression of disease or death, or censoring at the date of last evaluable disease assessment.
  • the increased progression- free survival is statistically significant.
  • the progression-free survival is increased a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the progression-free survival is increased compared to a group of patients who did not receive curative intent therapy.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • the methods provided herein result in an increased progression- free survival in a population of patients with muscle invasive bladder cancer of about 8 months to about 14 months, about 9 months to about 16 months, about 9 months to about 13 months, or about 10 months to about 14 months.
  • the progression-free survival in the population of patients is about 10, about 11, about 12, about 13, or about 14 months. In some embodiments, the progression-free survival in the population of patients is about 13.5 months.
  • the complete response rate in the population of patients is about 20% to about 40%. In some embodiments, the complete response rate in the population of patients is between about 20% and 25%, about 25% and about 30%, about 30% and about 35%, or about 35% and about 40%. In some embodiments, the complete response rate is at least about 30%, such as about 31.4%. In some embodiments, the complete response is defined by no evidence of intravesical disease by cystoscopy and biopsy and no evidence of pathological nodal involvement >10 mm.
  • the partial response rate in the population of patients is about 5% to about 10%. In some embodiments, the partial response rate in the population of patients is about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, or about 9% to about 10%. In some embodiments, the partial response rate at least about 8%, such as about 8.6%. In some embodiments, the partial response is defined by downstaged intravesical disease and no evidence of pathologic nodal involvement >10 mm.
  • the rate of stable disease in the population of patients is about
  • the rate of stable disease in the population of patients is about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30%. In some embodiments, the rate of stable disease in the population of patients is at least about 17%, such as about 17.1%. In some embodiments, stable disease is defined by no change in intravesical disease and no evidence of pathologic nodal involvement >10 mm.
  • the rate of progressive disease in the population of patients is about 10% to about 30%. In some embodiments, the rate of progressive disease in the population of patients is about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30%. In some embodiments, the rate of progressive disease in the population of patients is about 17.1%.
  • progressive disease is defined by any one of no evidence of intravesical disease by cystoscopy and biopsy and evidence of new pathologic nodal disease >10 mm; downstaged intravesical disease and evidence of new pathologic nodal disease >10 mm; increased burden of intravesical disease visually or pathologically and no evidence of pathologic nodal involvement >10 mm; increased burden of intravesical disease visually or pathologically and evidence of new pathological nodal disease >10 mm; or no change in evidence in intravesical disease and evidence of new pathologic nodal disease >10 mm.
  • the methods provided herein further comprise procedural interventions for symptom control.
  • symptom control is assessed based on the bladder symptom and toxicity grading system in which subjects are asked to assess their symptoms every 3 weeks during the induction period, and at once monthly intervals during the maintenance period.
  • the symptom comprises frequent urination, nocturia, hematuria and/or dysuria/pain.
  • the bladder symptom and toxicity grading system comprises Grades 0, 1, 2, and 3.
  • Grade 0 comprises a urinary frequency of less than 1 time per 2 hours, 0-1 nocturia events, and no hematuria or dysuria/pain.
  • Grade 1 comprises urinary frequency of 1 time per 2 hours, 2-3 nocturia events, occasional hematuria, and mild dysuria/pain.
  • Grade 2 comprises urinary frequency of 2 to 3 times per hour, 4-6 nocturia events, continuous hematuria, and moderate dysuria/pain.
  • Grade 3 comprises urinary frequency of more than 4 times per hour, 7 or more nocturia events, hematuria comprising clots and/or obstructions, and severe dysuria/pain.
  • the procedural interventions for symptom control can include, but are not limited to, TURBT, fulguration, cauterization, hemostatic agent instillation, hyperbaric oxygen, blood transfusion, nephrostomy catheter, hypogastric artery embolization, radiotherapy or palliative radiotherapy, or intravesical or IV chemotherapy.
  • time to intervention for symptom control is defined as the time from the date of the first TAR-200 insertion to the date of intervention for symptom palliation.
  • time to intervention for the 25 th percentile of the population of patients is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or greater than 5 months.
  • the time to intervention for the 25 th percentile of the population of patients is at least about 3.7 months.
  • the methods provided herein result in improved health-related quality of life (HRQoL).
  • the Functional Assessment of Cancer Therapy - Bladder Cancer (FACT-BL) is used to evaluate HRQoL.
  • the FACT-BL is a patient-reported outcome (PRO) measure comprising multiple questions designed to measure five domains in bladder cancer patients: Physical, social, emotional, functional well-being and bladder cancer subscale.
  • the FACT-BL is assessed at screening, after the second TAR-200 removal during the induction period, at each quarterly TAR-200 removal during the maintenance period, and at the Final Safety Follow-up Visit.
  • local administration of gemcitabine for a prolonged period maintains or improves HRQoL.
  • the HRQoL in the population of patients is higher than the HRQoL in a group of patients who did not receive curative intent therapy.
  • the FACT-BL score in the population of patients is between about 70 and about 140. In some embodiments, the FACT-BL score in the population of patients is about 70 to about 80, about 80 to about 90, about 90 to about 100, about 100 to about 110, about 110 to about 120, about 120 to about 130, about 130 to about 140. In some embodiments, the FACT-BL score in the population of patients is about 117.4.
  • a method of treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, and improving symptom control in the individual; increasing time to intervention for symptom control in the individual; reducing post-treatment interventions for the management of local symptoms in the individual; increasing overall survival in the individual; increasing the duration of response in the individual; increasing time to progression in the individual; and/or increasing the progression free survival of the individual.
  • the overall survival, duration of response, time to progression, and/or progression free survival is increased compared to the expected overall survival, duration of response, time to progression and/or progression free survival of the standard of care.
  • a method of increasing survival of an individual with muscle invasive bladder cancer comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein the survival of the individual is increased compared to the expected survival time if the individual had received no care, or the expected survival of the individual if the individual had received the standard of care.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein such treatment is safe and well-tolerated.
  • a method of administering a safe and tolerable treatment for muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times.
  • less than 20% of individuals within a patient population receiving such treatment experience a treatment emergent adverse event.
  • the percentage of individuals within a patient population received such treatment experiencing a treatment emergent adverse event is about 20%, about 15%, about 10%, about 5%, or about 0%.
  • the individual does not experience a treatment emergent adverse event.
  • the individual does not experience a renal or urinary disorder.
  • the individual does not experience increased urinary frequency, nocturia, urethral syndrome, and/or an infection and infestation during treatment.
  • the individual does not experience dysuria and/or a urinary tract infection during treatment.
  • provided herein is a method of treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein such treatment reduces the incidence of adverse events compared to systemic therapy. In some embodiments, such treatment reduces the incidence of adverse events compared to the standard of care.
  • the individual receiving such treatment does not experience a renal or urinary disorder, increased urinary frequency, nocturia, urethral syndrome, and/or an infection and infestation during treatment. In some embodiments, the individual does not experience dysuria and/or a urinary tract infection during treatment.
  • the treatment emergent adverse event is a renal or urinary disorder.
  • the renal or urinary disorder is selected from the group consisting of dysuria, pollakiuria, nocturia, urethral syndrome, acute kidney injury, haematuria, micturition urgency, urge incontinence, and urinary incontinence.
  • the treatment emergent adverse event is a gastrointestinal disorder.
  • the gastrointestinal disorder is abdominal pain.
  • the treatment emergent adverse event is a general disorder or an administration site condition.
  • the general disorder or an administration site condition comprises chills or pyrexia.
  • the treatment emergent adverse event is an infection or infestation.
  • the infection or infestation is selected from the group consisting of asymptomatic bateriuria, cystitis, and urosepsis.
  • the treatment emergent adverse event is a musculoskeletal or connective tissue disorder.
  • the musculoskeletal or connective tissue disorder comprises muscle spasms.
  • the treatment emergent adverse event is a reproductive system or breast disorder.
  • the reproductive system or breast disorder comprises penile burning sensations.
  • the individual is tolerant of the intravesical drug delivery device indwelling for the designated period of time and does not require removal of the intravesical drug delivery device prior to the scheduled date of removal. In some embodiments, less than 6% of individuals within a patient population receiving such treatment require removal of the intravesical drug delivery device prior to the scheduled date of removal. In some embodiments, the percentage of individuals within a patient population receiving such treatment requiring the removal of the intravesical drug delivery device prior to the scheduled date of removal is about 6%, about 5%, about 4%, about 3%, about 2%, about 1% or about 0%.
  • the methods provided herein include administering gemcitabine using an intravesical device.
  • the intravesical device is configured to be deployed into the bladder through the working channel of a catheter, cystoscope, or other deployment instrument positioned in the urethra.
  • the intravesical device is elastically deformable between a deployment shape for passage through the deployment instrument and a bladder retention shape in which the device (i) resists becoming entrained in urine and excreted when the individual voids, and (ii) intended to be tolerable to the individual, e.g., does not overly press on the bladder wall, or enter the ureter orifices (see, e.g., FIG. 5).
  • Such intravesical devices are known in the art.
  • the intravesical device is one described in one or more of U.S. Patent No. 10,543,166, U.S. Patent No. 9,283,361, U.S. Patent No. 8,679,094, U.S. Patent No. 10,857,336, U.S. Patent No. 9,457,176, U.S. Patent No. 8,690,840, U.S. Patent No. 9,107,816, U.S. Patent No. 10,137,287, U.S. Patent No. 9,814,671, U.S. Patent No. 10,729,823, U.S. Patent No. 10,315,019, U.S. Patent No. 10,933,170, U.S. Patent No. 10,737,078, U.S. Patent No. 10,894,150, and U.S. Patent No. 11,020,575, which are incorporated herein by reference in their entirety.
  • the intravesical device may release the gemcitabine continuously to achieve a concentration of the drug in the bladder that produces a sustained, therapeutically effective concentration of the drug in urine in the bladder as described in the methods provided herein.
  • the intravesical device may release the gemcitabine in an amount of about 0.5 mg/day to about 50 mg/day, about 1 mg/day to about 40 mg/day, about 3 mg/day to about 30 mg/day, about 5 mg/day to about 20 mg/day, about 1 mg/day to about 15 mg/day, about 10 mg/day to about 40 mg/day, or about 20 mg/day to about 40 mg/day.
  • these release rates are provided over a treatment period as described herein.
  • these release rates are provided over a delivery period from 1 day to 21 days. In certain embodiments, these release rates are provided over a delivery period from 1 day to 7 days. In certain embodiments, these release rates are provided over a delivery period from 1 day to 14 days. In certain embodiments, these release rates are provided over a delivery period from 7 days to 14 days. In certain embodiments, these release rates are provided over a delivery period from 7 days to 21 days. In certain embodiments, these release rates are provided over a delivery period from 14 days to 21 days. In certain embodiments, these release rates are provided over a delivery period of about 7 days. In certain embodiments, these release rates are provided over a delivery period of about 14 days. In certain embodiments, these release rates are provided over a delivery period of about 21 days.
  • the intravesical device comprises a device body, which may be a housing, and a drug payload which includes a suitable amount of the gemcitabine (e.g. 225 mg).
  • the drug payload may be referred to herein as a dosage form.
  • the drug payload may be contained in a lumen, or reservoir, within the device body.
  • the device body, in combination with the form and formulation of the drug payload, may control release/delivery of the gemcitabine into the bladder.
  • the intravesical device releases the gemcitabine. Release may occur, as described above, due to an osmotic pressure gradient between the interior and exterior of the device, the drug passing through one or more orifices or passing pores in the device under the force of osmotic pressure.
  • the material(s) used to form the device body may be water permeable so that solubilizing fluid (e.g., urine) can diffuse into the intravesical device to contact the drug pay load, e.g., enter a drug reservoir portion to solubilize the nonliquid forms of the gemcitabine contained within the intravesical device following its deployment into the bladder.
  • solubilizing fluid e.g., urine
  • silicone, certain thermoplastic polyurethanes, or other biocompatible elastomeric materials may be used.
  • the device body may be formed, at least in part, of a water-impermeable material.
  • the drug payload may be housed in the intravesical device in various forms, which may depend on the particular mechanism by which the device controllably releases the gemcitabine into fluid (e.g., urine) in the bladder.
  • the drug is provided in a solid, form, which advantageously may facilitate stable storage of the drug before the device is used and advantageously may enable the drug payload of the device to be stored in smaller volume than would be possible if the drug were housed in the form of a liquid solution.
  • the non-liquid form is a tablet (e.g., mini-tablets).
  • the intravesical device body includes a drug reservoir lumen.
  • the drug reservoir lumen hold one or several drug tablets or other solid drug units, wherein at least a portion of the tablets/units includes gemcitabine.
  • the device holds from about 10 to 100 cylindrical drug tablets, such as minitablets.
  • the mini-tablets each have a diameter of about 1.0 to about 3.3 mm, such as about 1.5 to about 3.1 mm, and a length of about 1.5 to about 4.7 mm, such as about 2.0 to about 4.5 mm.
  • the drug is in the form of a plurality of tablets, such as mini-tablets described in U.S. Patent No. 8,343,516, which is incorporated by reference herein.
  • the intravesical device comprises gemcitabine minitablets and osmotic minitablets. In some embodiments, the intravesical device comprises a plurality of gemcitabine minitablets sufficient to achieve 225 mg gemcitabine (free base equivalent). In some embodiments, the gemcitabine mini tablets further comprise urea. In some embodiments, the osmotic minitablets comprise urea as an osmotic agent. In some embodiments, the intravesical device comprises a plurality of osmotic minitablets. In some embodiments, the intravesical device comprises a plurality of osmotic minitablets sufficient achieve the desired gemcitabine release rate.
  • the intravesical device is configured to provide controlled release of the gemcitabine by osmotic pressure, as described, for example, in U.S. Patent No. 10,729,823, which as noted above is incorporated by reference herein.
  • the intravesical device includes a housing defining a reservoir; a first unit (e.g., a first plurality of tablets) contained within the reservoir, the first unit comprising gemcitabine; and a second unit (e.g., a second plurality of tablets) contained within the reservoir, the second unit comprising a functional agent and not comprising gemcitabine.
  • One or more of the first unit tablets may fill a length from about 1 cm to about 5 cm of the lumen of the tube, and one or more of the second unit tablets may fill a length from about 10 cm to about 14 cm of the lumen of the tube.
  • the functional agent is a substance that facilitates in vivo release of the drug from the housing.
  • it may be an osmotic agent, such as urea.
  • the housing is in the form of an elongated elastomeric tube having a lumen (i.e., the reservoir) in which all of the first and second tablets are aligned and contained, wherein the elastomeric tube includes one or more apertures or microchannels configured to provide release of the gemcitabine in vivo by osmotic pressure.
  • the intravesical device comprises a laser drilled orifice.
  • the orifice is centered over the gemcitabine minitablets.
  • the orifice is centered over the gemcitabine minitablets with osmotic minitablets on either side of the gemcitabine minitablets.
  • the intravesical device comprises a unit concentration of about 225 mg of gemcitabine.
  • 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 of gemcitabine) to the individual over about a seven day period, or about a fourteen-day period, or about a three- week period.
  • the intravesical device is a TAR-200/gemcitabine product, an intravesical drug delivery system consisting of two components: (i) the drug constituent, which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent; and (ii) the device constituent, which is comprised of a dual lumen silicone part with a single laser-machined orifice and a superelastic nitinol wire (as shown in FIG. 5). The large lumen of the silicone part contains the gemcitabine and urea minitablets and serves as an osmotic pump to release drug in a controlled manner.
  • the drug constituent which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent
  • the device constituent which is comprised of a dual lumen silicone part with a single laser-machined orifice
  • the smaller lumen contains a nitinol wire in a predefined coil form to provide retention of the intravesical drug delivery system in the individual’s bladder during the indwelling period.
  • the device is elastically deformable between a relatively straightened shape suited for insertion through the urethra of a patient and into the patient's bladder and a retention shape suited to retain the device within the bladder.
  • the TAR- 200 product can be manually uncurled and loaded into a urinary placement catheter. As the TAR-200 product exits the urinary placement catheter and is deployed into the bladder, the product returns to its retention shape.
  • a drug delivery system comprising gemcitabine in a format to be administered every three weeks to an individual four times that results in an increase in the overall survival in a population of patients who have received such treatment.
  • the increase in overall survival is longer than patients who did not receive or were ineligible for curative-intent therapy.
  • the increase in overall survival is at least 12 months in a population of patients that have muscle invasive bladder cancer.
  • a drug delivery system comprising gemcitabine in a format to be administered every three weeks to an individual four times that results in an increased duration of response in a population of patients with muscle invasive bladder cancer who have received treatment with local and continuous administration of gemcitabine.
  • the increased duration of response allows the individual to receive fewer rounds and less chemotherapy overall and enables the individual to be treated in a maintenance therapy regimen and/or for the individual to undergo periodic (such as quarterly) surveillance.
  • the duration of response is increased in a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the duration of response is increased compared to a group of patients who did not receive curative intent therapy.
  • a drug delivery system comprising gemcitabine in a format to be administered every three weeks to an individual four times that results in an increased time to progression in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • disease progression comprises an upstaging in the tumor.
  • the increased time to progression is statistically significant.
  • the time to progression is increased in a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the time to progression is increased compared to a group of patients who did not receive curative intent therapy.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • a drug delivery system comprising gemcitabine in a format to be administered every three weeks to an individual four times that results in an increased progression-free rate in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • the increased progression-free rate is statistically significant.
  • the progression-free rate is increased a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the progression-free rate is increased compared to a group of patients who did not receive curative intent therapy.
  • the progression- free rate is the progression-free rate of “responders” i.e.
  • a responder is an individual who did not show disease progression within a particular time frame.
  • the progression-free rate is the progression-free rate 6 months after treatment.
  • the progression-free rate is the progression-free rate 12 months after treatment.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • an article of manufacture comprising a packaging material and an intravesical system comprising an intravesicular (intravesical) device comprising 225 mg gemcitabine and a package insert comprising instructions for use according to the methods disclosed herein and/or describing the patient benefits disclosed herein (e.g., overall survival, progression-free survival, duration of response, time to progression, progression-free rate, complete response, partial response, overall response, duration of response).
  • the article of manufacture further comprises a urinary placement catheter.
  • the urinary placement catheter comprises a catheter and a stylet.
  • the article of manufacture further comprises a lubricant or a syringe.
  • the instructions for use provide instructions for administering a device comprising 225 mg gemcitabine according to the methods provided herein.
  • an article of manufacture comprising a drug delivery system comprising 225 mg gemcitabine and instructions for administering the drug delivery system for three weeks.
  • the article of manufacture comprises instructions for inserting the system into the bladder of an individual and removing the device three weeks later. In some embodiments, the article of manufacture comprises instructions for inserting the system into the bladder of an individual and removing the device three weeks later four times.
  • the benefits of the article of manufacture comprising a drug delivery system comprise an increase in the overall survival in a population of patients who have received such treatment. In some embodiments, the increase in overall survival is longer than patients who did not receive or were ineligible for curative-intent therapy. In some embodiments, the increase in overall survival is at least 12 months in a population of patients that have muscle invasive bladder cancer. [0176] In some embodiments, the benefits of the article of manufacture comprising a drug delivery system comprise an increased duration of response in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • the increased duration of response allows the individual to receive fewer rounds and less chemotherapy overall and enables the individual to be treated in a maintenance therapy regimen and/or for the individual to undergo periodic (such as quarterly) surveillance.
  • the duration of response is increased in a population of patients who have received such therapy compared to a group of patients who have received the standard of care. In some embodiments, the duration of response is increased compared to a group of patients who did not receive curative intent therapy.
  • the benefits of the article of manufacture comprising a drug delivery system that results in an increased time to progression in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • disease progression comprises an upstaging in the tumor.
  • the increased time to progression is statistically significant.
  • the time to progression is increased in a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the time to progression is increased compared to a group of patients who did not receive curative intent therapy.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • the benefits of the article of manufacture comprising a drug delivery system comprise an increased progression-free rate in a population of patients with muscle invasive bladder cancer who have received treatment with local administration of gemcitabine.
  • the increased progression-free rate is statistically significant.
  • the progression-free rate is increased a population of patients who have received such therapy compared to a group of patients who have received the standard of care.
  • the progression-free rate is increased compared to a group of patients who did not receive curative intent therapy.
  • the progression-free rate is the progression-free rate of “responders” i.e. those who have responded to treatment with local gemcitabine.
  • a responder is an individual who did not show disease progression within a particular time frame.
  • the progression-free rate is the progression-free rate 6 months after treatment.
  • the progression-free rate is the progression-free rate 12 months after treatment.
  • the individual and/or population of patients is unfit or ineligible for curative intent therapy.
  • the individual and/or population of patients is elderly or frail.
  • the article of manufacture comprises a packaging material and a TAR-200 drug delivery system and a urinary placement catheter comprising a catheter and a stylet.
  • TAR-200 is an intravesical drug delivery system consisting of two components: (i) the drug constituent, which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent; and (ii) the device constituent, which is comprised of a dual lumen silicone part with a single laser-machined orifice and a superelastic nitinol wire (“wireform”), see also FIG. 5.
  • the large lumen of the silicone part contains the gemcitabine and urea minitablets and serves as an elementary osmotic pump to release drug in a controlled manner.
  • the smaller lumen contains the nitinol wire in a predefined form to provide retention of the system in the bladder during the indwelling period.
  • the intravesical device comprises a deployment shape.
  • the device and the urinary placement catheter are packaged in separate pouches (e.g., Tyvek pouches). In some embodiments, the device and the urinary placement catheter are packaged together in the same pouch (e.g., a Tyvek pouch).
  • kits for carrying out any methods described herein are provided herein.
  • kits comprising an intravesical system comprising a gemcitabine delivery system containing 225-mg free base equivalents of gemcitabine and a package insert comprising instructs for use according to any one of methods described herein and/or describing the patient benefits disclosed herein (e.g., overall survival, progression-free survival, duration of response, time to progression, progression- free rate, complete response, partial response, overall response, duration of response).
  • the kit further comprises a urinary placement catheter.
  • the urinary placement catheter comprises a catheter and a stylet.
  • the kit further comprises a lubricant or a syringe.
  • the intravesical device comprises a deployment shape.
  • the device and the urinary placement catheter are packaged in separate pouches (e.g., Tyvek pouches).
  • the device and the urinary placement catheter are packaged together in the same pouch (e.g., a Tyvek pouch).
  • the kit further comprises instructions for inserting the gemcitabine delivery system into the bladder of an individual, and/or instructions for removing the gemcitabine delivery system.
  • a method of treating of treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein such treatment is safe and well- tolerated.
  • a method of treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein administering such treatment to a population of patients results in an overall survival of at least 12 months in the population of patients; administering such treatment to a population of patients results in a duration of response of at least 12 months in the population of patients; administering such treatment to a population of patients results in a time to progression of at least 12 months in the population of patients; administering such treatment to a population of patients results in a progression-free rate among responders in the population of patients of at least 80% at 6 months; and/or administering such treatment to a population of patients results in a progression-free survival of at least 8 months in the population of patients.
  • a method of treating muscle invasive bladder cancer in an individual comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, and improving symptom control in the individual; increasing time to intervention for symptom control in the individual; reducing post-treatment interventions for the management of local symptoms in the individual; increasing overall survival in the individual; increasing the duration of response in the individual; increasing time to progression in the individual; and/or increasing the progression free survival of the individual.
  • a method of increasing survival of an individual with muscle invasive bladder cancer comprising administering about 225 mg of gemcitabine locally to the bladder of the individual for about three weeks four times, wherein the survival of the individual is increased compared to the expected survival time if the individual had received no care, or the expected survival of the individual if the individual had received the standard of care.
  • any one of embodiments 1-15 comprising a dosing schedule of at least 12 weeks comprising i) inserting a first intravesical drug delivery system into the bladder on day 0, and removing the first intravesical drug delivery system on about day 21 ; ii) inserting a second intravesical drug delivery system on about day 21 after removing the first intravesical drug delivery system, and removing the second intravesical drug delivery system on day about 42; iii) inserting a third intravesical drug delivery system on about day 42 after removing the second intravesical drug delivery system, and removing the third intravesical drug delivery system on about day 63; iv) inserting a fourth intravesical drug delivery system on about day 63 after removing the third intravesical drug delivery system, and removing the fourth intravesical drug delivery system on about day 84; and wherein each intravesical drug delivery system comprises an intravesical device comprising about 225 mg of gemcitabine.
  • assessing the response is selected from the group consisting of cystoscopic examination of visual lesions, computed tomography (CT) imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), and pathologic staging of a bladder biopsy specimen.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • [0216] 34 The method of embodiment 33, wherein the progression-free rate among responders in the population of patients receiving such treatment is about 70.5% at 12 months.
  • [0229] 47 The method of embodiment 46, wherein the rate of progressive disease in the population of patients is about 17.1%.
  • 48 The method of embodiment 46 or 47, wherein progressive disease is defined by no evidence of intravesical disease by cystoscopy and biopsy and evidence of new pathologic nodal disease >10 mm; downstaged intravesical disease and evidence of new pathologic nodal disease >10 mm; increased burden of intravesical disease visually or pathologically and no evidence of pathologic nodal involvement >10 mm; increased burden of intravesical disease visually or pathologically and evidence of new pathological nodal disease >10 mm; or no change in evidence in intravesical disease and evidence of new pathologic nodal disease >10 mm.
  • assessing the response comprises performing a cystoscopy, a biopsy, and/or imaging.
  • the drug delivery system comprises a device body comprising (i) a drug reservoir tube that defines a drug reservoir lumen, and (ii) a retention frame tube that defines a retention frame lumen; a plurality of tablets which comprise gemcitabine, the tablets positioned in the drug reservoir lumen; and a retention frame positioned in the retention frame lumen.
  • the drug reservoir tube comprises an aperture in a sidewall of the drug reservoir tube, the aperture being configured to release the drug following at least partial solubilization of the plurality of the drug tablets.
  • kits comprising a drug delivery system comprising about 225 mg gemcitabine and instructions for use according to the method of any one of embodiments 1-110.
  • a drug delivery system for treating muscle invasive bladder cancer in an individual comprising about 225 mg of gemcitabine to be locally to the bladder of the individual for about three weeks four times, wherein administering the drug delivery system to a population of patients results in an overall survival of at least 12 months in the population of patients; administering the drug delivery system to a population of patients results in a duration of response of at least 12 months in the population of patients; administering the drug delivery system to a population of patients results in a time to progression of at least 12 months in the population of patients; administering the drug delivery system to a population of patients results in a progression-free rate among responders in the population of patients of at least 80% at 6 months; and/or administering the drug delivery system to a population of patients results in a progression-free survival of at least 8 months in the population of patients.
  • a drug delivery system for treating muscle invasive bladder cancer in an individual comprising about 225 mg of gemcitabine to be locally to the bladder of the individual for about three weeks four times, wherein administering the drug delivery system to a population of patients is safe and well-tolerated.
  • a study called TAR-200-103 was a prospective, multicenter, open-label, single-arm, global phase 1 study in which eligible patients received up to 4 consecutive 21 -day cycles of TAR-200 during an 84-day induction period within 7 weeks after transurethral resection of bladder tumor (TURBT) (FIG. 1).
  • TURBT transurethral resection of bladder tumor
  • TAR-200 is an intravesical drug delivery system consisting of two components: (i) the drug constituent, which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent; and (ii) the device constituent, which is comprised of a dual lumen silicone part with a single laser-machined orifice and a superelastic nitinol wire (“wireform”). Patients were eligible for 3 optional additional quarterly maintenance cycles starting on day 180, if judged by the investigator to be in the patient’s best interest. A final safety follow-up visit occurred after the maintenance period (30 days after last TAR-200 removal). Patients then entered an optional 24-month surveillance period to monitor for recurrence and OS.
  • the drug constituent which consists of gemcitabine minitablets (225 mg, free base equivalent) and osmotic minitablets containing urea as the osmotic agent
  • the device constituent which is comprised of a dual lume
  • Eligible patients were diagnosed with urothelial MIBC (cT2-cT3bN0M0); those with mixed histology had a documented dominant transitional cell pattern. Micropapillary, sarcomatoid, and adenocarcinoma variants were excluded. Enrolled patients had a life expectancy of >4 months, had undergone endoscopically visible complete resection via TURBT, were deemed unfit for RC by principal investigator assessment (with a mortality risk of RC >3%, as estimated using the American College of Surgeons risk calculator), and refused or were considered medically ineligible for cisplatin-based chemotherapy or radical radiotherapy (>50 Gy).
  • Exclusion Criteria Subjects were excluded from study entry if any of the following exclusion criteria existed at the time of enrollment.
  • TAR-200 was dosed in 4 consecutive 21 -day cycles, with the first TAR-200 inserted on study day 0 and removed on day 21. Another TAR-200 was inserted the same day.
  • Urinalyses and urine cultures were performed at each TAR-200 insertion to rule out urinary tract infection. This cycle was repeated every 21 days, with the fourth TAR-200 removed on day 84.
  • AEs adverse events
  • IPEs investigational product events
  • cystoscopy findings were either patient-reported or identified during study visits and monthly telephonic interviews and were recorded from study day 0 through the final safety follow-up visit, including an evaluation on day 95.
  • IPEs included any observation of TAR-200 not performing as intended. Cystoscopy findings were considered adverse if evidence of urothelial bleeding or bladder stones were noted.
  • Treatment-emergent AEs were defined as any new AE, or worsening of any pre-existing AE, that occurred after initiation of the first dose of TAR- 200.
  • the TEAE period extended for 30 days after discontinuation of study treatment.
  • AEs were coded using the Medical Dictionary for Regulatory Activities, and their severity was categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. AEs were also assessed as being related to the drug or device constituent or to the insertion/removal procedure by the investigator.
  • Tolerability was defined as not requiring early /unscheduled TAR-200 removal due to meeting any predefined safety criteria (ie, grade >2 hematuria, aseptic cystitis, severe opportunistic infections, urinary tract infection [UTI], allergic reaction, signs of systemic gemcitabine toxicity) or any other TAR- 200-related TEAEs.
  • predefined safety criteria ie, grade >2 hematuria, aseptic cystitis, severe opportunistic infections, urinary tract infection [UTI], allergic reaction, signs of systemic gemcitabine toxicity
  • CR complete response
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • DOR duration of response
  • OS bladder-related symptom control
  • time to symptom control intervention time to progression
  • PFS progression-free survival
  • Safety, tolerability, and early efficacy are descriptively summarized.
  • descriptive statistics including the mean, median, minimum, and maximum were provided.
  • Categorical variables were summarized using frequency counts and percentages.
  • time-to-event variables the Kaplan-Meier method was used to calculate the distribution (median and Kaplan-Meier curve). Analyses were performed on all enrolled and treated patients as of the data cutoff date. As this was a Phase lb study, the predetermined sample size of approximately 30 patients per protocol was not based on statistical considerations and there was no hypothesis testing nor p-values generated. Duration of response was defined as the time from first observation of CR or PR to the first observation of progressive disease or death in patients that had a response.
  • Baseline patient characteristics are presented in Table 2. The median age was 84 years and mean body mass index was 28.2 kg/m 2 . Most patients were male and white, and the majority had a history of tobacco use; 45.7% (16/35) and 57.1% (20/35) of patients had an Eastern Cooperative Oncology Group performance status >3 and Charlson Comorbidity Index >2, respectively. A prior history of intravesical Bacillus Calmette-Guerin was reported by 6 (17.1%) patients.
  • TAR-200-related TEAEs occurred in 15 (42.9%) patients with dysuria (20.0%), urinary frequency (14.3%), nocturia (8.6%), and urethral syndrome (8.6%) the most common (table 2).
  • the progression-free rate of patients still in response was estimated to be 92.3% at 6 months and 70.5% at 12 months using the Kaplan-Meier method.
  • Median time to disease progression was 13.5 months (95% CI 6.2-NE) and median PFS was 9.5 months (95% CI 4.1-15.6) (FIG. 3B).
  • TAR-200 is safe and well tolerated in this elderly patient population (median age 84; ECOG 3-4, 46%).
  • This safety profile is consistent with TEAEs frequently noted after intravesical instillations of gemcitabine and those commonly observed with indwelling urethral catheters and ureteral stents.
  • TEAEs leading to death were considered related to TAR-200, only 1 TAR-200-related TEAE led to study discontinuation, and 1 patient reported SAEs that the investigator considered related to the drug delivery system. Placement of TAR-200 into the bladder was successful in all patients, only 2 patients were considered not tolerant of TAR- 200 and no IPEs were reported. Although clot evacuation and blood transfusion were required in 1 patient each, this is considerably lower than in patients who received no curative-intent treatment. TEAEs observed in this elderly and frail cohort of patients with MIBC were as expected, with no unanticipated safety issues attributed to treatment with TAR-200.
  • TAR-200 was safe and well tolerated in elderly patients with primarily cT2 MIBC who either refused or were unfit for curative-intent therapy. Intravesical TAR-200 monotherapy had promising preliminary effects on patient outcomes, warranting further study as a therapeutic option in this population of patients with predominantly cT2 MIBC.
  • Example 1 Additional data was obtained from the TAR-200-103 study described in Example 1.
  • the present example describes analyses of the TAR-200-103 study from the study period of 15 December 2017 (Date first subject signed informed consent form) to 15 September 2022 (last participant last visit).
  • the objectives of this study were to: 1) Evaluate both the safety and tolerability of up to 4 dosing cycles of TAR-200 for approximately 21 days per dosing cycle in the induction period, 2) Evaluate the anti-tumor effects of TAR-200, 3) Assess symptom control in subjects receiving TAR-200, 4) Evaluate time to onset of progression of disease and time to intervention for symptom control, 5) Assess overall survival at 12, 24, and 36 months.
  • Efficacy Evaluation Clinical response was assessed at the end of the induction period (Month 3/Study Day 84) based on cystoscopic examination of visual lesions, evaluation of metastases by computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scans of the chest/abdominal/pelvis, and by pathologic staging of the bladder biopsy specimen.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • the definitions of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) derived from these assessments are defined in Table 5:
  • Cystoscopy assessments and CT, MRI, or PET scans were subsequently performed approximately every 3 months during the maintenance period to monitor subjects for disease progression. Additional biopsies could be performed if needed at the discretion of the investigator.
  • Subjects were also assessed for symptom control (based on the bladder symptom and toxicity grading system) every 3 weeks during the induction period and approximately every month during the maintenance period.
  • FACT-BL Functional Assessment of Cancer Therapy - Bladder Cancer
  • PRO patient- reported outcome
  • HRQoL health-related quality of life
  • Safety Evaluation was assessed throughout the induction and maintenance periods based on the incidence and severity of treatment-emergent adverse events (TEAEs), Investigational Product Events (IPEs), cystoscopy findings, and changes in clinical laboratory analyte values and vital sign measurements.
  • TEAEs treatment-emergent adverse events
  • IPEs Investigational Product Events
  • cystoscopy findings cystoscopy findings
  • changes in clinical laboratory analyte values and vital sign measurements were assessed throughout the induction and maintenance periods based on the incidence and severity of treatment-emergent adverse events (TEAEs), Investigational Product Events (IPEs), cystoscopy findings, and changes in clinical laboratory analyte values and vital sign measurements.
  • 24-Month Surveillance Period During the 24-month surveillance period, study visits were scheduled every 6 months ( ⁇ 21 days) to assess overall survival and to perform a CT, MRI, or PET scan to evaluate disease progression/response.
  • Efficacy Analyses The proportion of subjects with CR, PR, SD, and PD at the end of the induction period (Month 3) was summarized, and the point estimate and corresponding 95% confidence intervals were provided for the overall response rate (CR+PR). Changes in bladder-related symptoms were presented in shift tables. Other efficacy endpoints included the time to procedural intervention for symptom control; the proportion of subjects undergoing procedural intervention; the time to disease progression; and progression— free and overall survival. Time-to-event endpoints were summarized using the Kaplan-Meier method. FACT-BL results were summarized descriptively and listed.
  • Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 24.1. Treatment-emergent adverse events, treatment-emergent serious adverse events (SAEs), TEAEs leading to TAR-200 removal, and TEAEs leading to death were summarized by System Organ Class and preferred term. TEAEs were also summarized by the United States National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; Version 5.0) severity grade and by relationship to (a) the Investigational Product (IP) (TAR-200) (drug and/or device constituent) and b) the procedure (Inserter and/or cystoscopy).
  • NCI National Cancer Institute
  • CCAE Common Terminology Criteria for Adverse Events
  • Study Population Overall, 35 subjects were enrolled and entered the induction period. All 35 subjects received at least 1 dose of TAR-200 and were included in the Full Analysis Set, Efficacy Analysis Set, and Safety Analysis Set.
  • the median number of dosing cycles received during the study was 5 (range: 1-7), with 12 subjects (34.3%) completing all 7 dosing cycles.
  • the mean number of days that TAR-200 was indwelling in the bladder was 107.0 days, and the mean number of days between first TAR-200 insertion and last TAR-200 removal was 222.5 days.
  • Clinical response was evaluated at the end of the induction period (Month 3) after 4 consecutive 21-day dosing cycles with TAR-200.
  • 31.4% (11/35 subjects) had a CR and 8.6% (3/35 subjects) had a PR, for an overall response rate of 40.0% (14/35 subjects).
  • Six subjects (17.1%) had SD and 6 subjects (17.1%) had PD.
  • Clinical response was evaluated at the end of the induction period (Month 3) following 4 consecutive 21-day TAR-200 dosing cycles.
  • 14 subjects (40%) had a response (31.4% had a CR and 8.6% had a PR).
  • the Kaplan-Meier estimated median duration of response in these 14 subjects was 14 months, and the estimated event-free rate (ie, proportion of subjects still in response) was 92.3% at 6 months, 70.5% at 12 months and 14.1% at 24 months.
  • the first TAR-200 was inserted transuretherally into the bladder on Study Day 0.
  • Study Day 21 On Study Day 21 ( ⁇ 3 days), the first TAR-200 was removed, and the second TAR-200 was placed on the same day.
  • This removal/replacement procedure was repeated for a third and fourth dosing cycle in the induction period on Study Days 42 ( ⁇ 3 days) and 63 ( ⁇ 3 days), respectively.
  • the fourth TAR-200 was removed on Study Day 84 ( ⁇ 3 days).
  • the study site staff contacted subjects on Study Day 95 ( ⁇ 7 days) to enquire about adverse events (AEs) or changes in concomitant medications/procedures.
  • AEs adverse events
  • Efficacy assessments performed during the study are summarized in FIG. 7. All subjects were assessed for clinical response at the end of the induction period (Month 3/Study Day 84) based on cystoscopic assessment of visual lesions, evaluation of metastases via computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scans of the chest/abdomen/pelvis, and pathologic staging of the bladder biopsy specimen.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • the definitions of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) derived from these assessments are defined in Table 5. Cystoscopy assessments and CT, MRI, or PET scans were subsequently performed approximately every 3 months during the maintenance period to monitor subjects for disease progression. Additional biopsies could be performed if needed at the discretion of the investigator.
  • Subjects were also assessed for symptom control (based on the bladder symptom and toxicity grading system) every 3 weeks during the induction period and approximately every month during the maintenance period. Procedural interventions for symptom palliation could be performed at the discretion of the investigator after the induction period.
  • FACT-BL Functional Assessment of Cancer Therapy - Bladder Cancer
  • PRO patient- reported outcome
  • HRQoL health-related quality of life
  • Safety and tolerability were evaluated throughout the induction and maintenance periods based on the incidence and severity of treatment-emergent adverse events (TEAEs), Investigational Product Events (IPEs), cystoscopy findings, and changes in clinical laboratory tests (chemistry, hematology, urinalysis, and urine culture) and vital sign measurements.
  • TEAEs treatment-emergent adverse events
  • IPEs Investigational Product Events
  • cystoscopy findings and changes in clinical laboratory tests (chemistry, hematology, urinalysis, and urine culture) and vital sign measurements.
  • TAR-200 is comprised of 2 components: a device constituent and drug constituent.
  • TAR-200 device constituent is comprised of medical grade silicone tubing, a preformed superelastic nitinol wireform housed in the small lumen, silicone elastomer spacers to form the drug compartment in the large lumen, and an ending sealed with silicone adhesive.
  • the drug compartment contains both gemcitabine and osmotic minitablets, with a payload of 225 mg gemcitabine free base equivalents.
  • TAR-200 is flexible, shaped like a “pretzel,” and is approximately 3.8 mm at its largest cross-sectional dimension.
  • Urinary Placement Catheter A disposable, co-packaged, single -use, sterile Urinary Placement Catheter for insertion of TAR-200 was provided by the Sponsor.
  • the Urinary Placement Catheter is a modified single -use intermittent urinary catheter consisting of a clear catheter and a green stylet. After the catheter is placed into the bladder, TAR-200 is loaded linearly into the clear catheter of the Urinary Placement Catheterand then advanced through the clear catheter into the bladder using the green stylet. TAR-200 returns to its original “pretzel-like” form after exiting from the Urinary Placement Catheter and is fully deployed into the bladder.
  • the screening CT, MRI, or PET scan must have been completed during screening or within 2 months prior to enrollment to confirm that there was no evidence of upper tract urothelial cell carcinoma, involvement of the pelvic lymph nodes, or any other metastases.
  • the type of scan (CT, MRI, or PET) used during the study should have been the same as that used to diagnose the subject prior to the study.
  • Multimodal study visit-to-visit imaging was allowed as long as the chosen imaging included the chest, abdomen and pelvis in the assessment.
  • TURBT and Biopsy/Pathology A TURBT was performed within 7 weeks prior to Study Day 0 to remove as much tumor as possible. Formal re-evaluation of the TURBT specimen was performed by the study site.
  • a cystoscopic biopsy sample (TURBT and/or cystoscopic cold-cup biopsy) was taken at the end of the induction period (Study Day 84 or Early Termination). After the induction period, additional TURBTs could be performed (see Section 3.8) and/or additional biopsy samples could be collected if clinically indicated (eg, if there was evidence of new or presumed tumor on cystoscopic examination).
  • TAR-200 could still be placed, if desired. In these cases, it was recommended that TURBT was performed around the time of TAR-200 removal (within 21 days of removal).
  • Patient-Reported Symptom Control was assessed based on the bladder symptom and toxicity grading system (see Table 7). Subjects were asked to assess their symptoms every 3 weeks during the induction period (at each TAR-200 insertion and each TAR- 200 removal), and at once monthly intervals during the maintenance period.
  • Clinical Response An assessment of clinical response was performed at the end of the induction period (Month 3/Study Day 84) based on a composite evaluation of cystoscopic assessment of visual lesions, evaluation of metastases by CT, MRI, or PET scans, and pathologic staging of the bladder biopsy specimen.
  • the definitions of CR, PR, SD, and PD derived from these assessments are defined in Table 5.
  • FACT-BL is a 39-item questionnaire used to assess HRQoL in patients with bladder cancer. This patient-reported scale evaluates 5 domains: physical well-being (PWB), social wellbeing (SWB), emotional well-being (EWB), functional well-being (FWB), and a bladder cancer subscale. Subjects completed the FACT-BE at screening, after the second TAR-200 removal during the induction period (Study Day 42 [or Early Termination]), at each quarterly TAR-200 removal during the maintenance period, and at the Final Safety Follow-up Visit.
  • PWB physical well-being
  • SWB social wellbeing
  • EWB emotional well-being
  • FWB functional well-being
  • Safety was evaluated during the induction and maintenance periods based on reporting of AEs, clinical laboratory tests (hematology, serum chemistry, urinalysis, and urine culture), IPEs, vital sign measurements, and cystoscopy findings.
  • Adverse Events were recorded starting from the first protocol-required cystoscopy (Study Day 0) through to the Final Safety Follow-up Visit (30 ⁇ 3 days after the last TAR- 200 removal). Adverse events occurring after signing of informed consent and before the protocol-required screening cystoscopy were reported as medical history.
  • Adverse events were either reported by the subject voluntarily or were obtained by means of interviewing subjects in a nondirected manner at study visits or during the monthly telephone calls performed during the maintenance period. Adverse event definitions, attributions, and severity criteria are listed in the protocol. The severity of each AE was assessed according to the NCI CTCAE Version 5.0.
  • Additional endpoints included a primary analysis to assess the safety and efficacy of TAR-200 in subjects using data available up to 1 year (induction + maintenance); an analysis of response duration; and an analysis of progression-free survival.
  • Clinical Response Clinical response was assessed at the end of the induction period (Month 3/Study Day 84) based on composite evaluation of cystoscopy assessments, CT7MRI/PET scans, and biopsy results. Definitions of CR, PR, SD, and PD are provided in Table 3.
  • the duration of response (defined as the time [in months] from first observation of CR/PR to the first observation of disease progression or death) was calculated in subjects who were responders (ie, overall response of CR or PR) using the Kaplan-Meier method. Responders without disease progression who were still alive at the end of the study were censored at the date of the last evaluable disease assessment where disease response was not considered as progression.
  • Symptom control was assessed based on the bladder symptom and toxicity grading system (see Table 2) as reported by the subject at the assessed time points. Changes in symptom grades from baseline (prior to first insertion of TAR- 200) to each postbaseline assessment and the overall worst post-baseline assessment were summarized in shift tables. Subjects with missing symptom control grades were also summarized in the shift tables.
  • Procedural Interventions for Symptom Palliation The time to procedural intervention for symptom palliation (as described further in Section 3.8) was analyzed using the Kaplan- Meier method. Time to treatment intervention was defined as the time from the date of the first insertion of TAR-200 to the date of the intervention for symptom palliation or censoring. Subjects without an intervention for symptom palliation at the end-of-study were censored at the date last known alive.
  • Time to progression defined as the time from the date of the first insertion of TAR-200 to the date of the first occurrence of PD or censoring. Subjects without PD at end of the study were censored at the date of the last evaluable disease assessment where disease response was not considered as progression.
  • Progression-free survival defined as the time from the date of the first insertion of TAR- 200 to the date of the first occurrence of progression of disease or death, or censoring. Subjects without progression and still alive at end-of-study were censored at the date of the last evaluable disease assessment where disease response was not considered as progression.
  • HRQoL Health-related Quality of Life
  • Adverse Events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 and summarized by System Organ Class (SOC) and preferred term.
  • MedDRA Medical Dictionary for Regulatory Activities
  • SOC System Organ Class
  • a TEAE was defined as any AE with onset occurring after initiation of the first dose of TAR-200 (or any AE that was present at baseline but worsened in intensity after initiation of dosing with the first TAR-200) with an onset no later than 30 days after discontinuation of study treatment (ie, 30 days after the last TAR-200 removal).
  • AEs were listed. By-subject listings also were provided for the following: AEs leading to death; SAEs; AEs leading to IP removal; and AEs leading to study discontinuation. Narrative descriptions were prepared for all AEs leading to death, treatment- emergent SAEs, TEAEs leading to study discontinuation, and TEAEs leading to IP removal.
  • Tolerability was defined as being tolerant of TAR-200 indwelling for the designated period of time and not requiring TAR-200 removal prior to the scheduled date of removal due to meeting any of the Subject Stopping Safety Criteria or other drug or device constituent related AEs.
  • TAR-200 was either not inserted or was removed if the subject experienced any of the following related to the IP (TAR-200) (Note: grading is based on the NCI CTCAE v5.0 grading criteria): Grade >2 hematuria not requiring transfusion, IV medication (ie, aminocaproic acid) or hospitalization for endoscopic, radiologic, or operative intervention. Note: in the event of Grade >2 hematuria that was clinically significant and persistent for >48 hours, a urine sample was to be collected to assess urine specific gravity, and urine electrolytes. Grade >2 clinical and cystoscopic signs of aseptic cystitis, defined as recurrent cystitis that did not require IV medication or hospitalization for endoscopic, radiologic, or operative intervention.
  • Grade >2 allergic reaction shortness of breath, generalized edema, etc.
  • system device constituent materials silicone, nitinol
  • drug gemcitabine
  • excipients povidone, urea, polyethylene oxide, FD&C Blue #1, and polyethylene glycol
  • TARIS Inserter materials thermoplastic elastomer, polyethylene, titanium dioxide, phthalocyanine green, copper [II] phthalocyanine.
  • Signs of systemic gemcitabine toxicity ie, hematological toxicity: absolute neutrophil count ⁇ 1000/mm3, platelet count ⁇ 50,000/mm3. Severe or medically-significant but not immediately lifethreatening opportunistic infections that required hospitalization or resulted in prolongation of hospitalization.
  • Grade >2 active UTI that the investigator believed to be clinically significant.
  • TAR-200 was removed, or the insertion of an additional TAR-200 was delayed for Grade >3 AEs not mentioned above which were assessed as related (to drug or device constituents) until such AEs returned to Grade ⁇ 1 or baseline.
  • Exclusions to this criterion included Grade 3 nausea and Grade 3-4 emesis that resolved within 2 days on optimum treatment and Grade 3- 4 laboratory abnormalities that did not result in hospitalization. Subjects whose related AEs did not return to Grade ⁇ 1 or baseline within 2 weeks of onset were to be permanently discontinued.
  • Two of the 7 subjects who discontinued the study due to an adverse event also had permanent premature TAR-200 removal.
  • 7 (20.0%) subjects did not complete study treatment but did not discontinue the study. Five of these subjects received 7 dosing cycles overall (but did not attend the Final Safety Follow-up Visit), 1 subject received 6 dosing cycles, and 1 subject received 3 dosing cycles.
  • 3 ECOG performance status grades can be interpreted as the following: 0 - fully active, able to carry on all pre-disease performance without restriction; 1 - restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2 - Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3 - Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4 - Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; 5 - Dead.
  • BMI body mass index
  • ECOG Eastern Cooperative Oncology Group
  • clinical staging was cT2 for all but 1 subject with a clinical staging of cT3.
  • Pathological staging at diagnosis was T2 for 27 subjects, T2a for 4 subjects, and T2b for 4 subjects.
  • Five subjects had concomitant CIS at the time of diagnosis and 7 subjects showed presence of hydronephrosis.
  • Most subjects (26/35) had 1 visible tumor at the time of diagnosis; 6 subjects had 2 or 3 visible tumors; and 3 subjects had 5 to 8 visible tumors.
  • Results of the Charlson Comorbidity Index assessment The total comorbidity score ranged from 0 to 9, and approximately half the subjects (20/35) had a comorbidity score of >2. At screening, 15 subjects were considered not or mildly ill, 11 were considered moderately ill, and 8 were considered severely ill (rating was missing for 1 subject).
  • Clinical Response The proportion of subjects meeting response criteria at the end of the induction period (Month 3) is summarized in Table 10. Response was assessed in all subjects who completed 4 TAR-200 dosing cycles and who underwent the biopsy/pathology assessment.
  • Duration of Response The duration of response was evaluated in the 14 subjects who had a response (CR or PR) at the end of the induction period based on the Kaplan-Meier method. Results are summarized in Table 11 and the Kaplan-Meier plot is provided in FIG. 8.
  • the Kaplan-Meier estimated event-free rate (ie, the percentage of subjects still in response) was 92.3% at 6 months, 70.5% at 12 months, 28.2% at 18 months and 14.1% at 24 months.
  • Duration of response is defined as the time (in months) from first observation of CR/PR to the first observation of progression or death, in subjects who are responders (i.e. best overall response of CR or PR).
  • Protocol Analysis Set were generally consistent with the results in the Efficacy Analysis Set.
  • Time to intervention is defined as the time from the date of the first insertion of TAR-200 to the date of the intervention for symptom palliation or censoring.
  • Time to progression is defined as the time from the date of the first insertion of TAR- 200 to the date of the first occurrence of progression of disease or censoring.
  • the Kaplan-Meier estimate of progression-free survival rate (ie, percentage of subjects not experiencing disease progression or death) was 68.2% at 6 months, 38.9% at 12 months, 13.4% at 24 months and 0 at 36 months.
  • PFS Progression-Free Survival
  • the Kaplan-Meier estimate of overall survival rate (ie, percentage of subjects remaining alive) was 88.6% at 6 months, 62.0% at 12 months, 51.6% at 24 months, and 47.9% at 36 months.
  • OS Overall survival
  • the compliance rate for the FACT-BL during the induction period was 94.3% (33 of 35 subjects) at baseline and 77.1% (27 of 35 subjects) after the second TAR-200 removal. Compliance rates decreased during the maintenance period and at the Final Safety Follow-up Visit.
  • the median FACT-BL total score at baseline was 105.8 (range: 83.8 and 136.3). After the second TAR-200 removal the median FACT-BL total score was 104.8 (range: 77.8 and 134.7). At the final maintenance follow-up, the median FACT-BL total score was higher at 117.4 (range: 74.8 and 134.0).
  • the median overall survival was 27.3 months.
  • the Kaplan-Meier estimate of overall survival rate (ie, percentage of subjects remaining alive) was 88.6% at 6 months, 62.0% at 12 months, 51.6% at 24 months, and 47.9% at 36 months.
  • the median FACT-BL total score at baseline was 105.8 (range: 83.8 and 136.3). At the final maintenance follow-up, the median FACT-BL total score was higher at 117.4 (range: 74.8 and 134.0).
  • Table 17 An overall summary of TEAEs observed during the induction and maintenance periods is provided in Table 17.
  • TEAEs leading to study discontinuation were considered related to TAR-200 or procedure, except for 1 nonserious TEAE (urge incontinence) that was considered related to TAR-200.
  • TEAEs classified as Grade 3 or higher were reported by 22 subjects (62.9%).
  • TEAEs (preferred terms) that were experienced by more than 1 subject (>5%) are summarized in Table 18.
  • TEAEs The most common TEAEs (preferred terms) (experienced by >15% of subjects) were dysuria (57.1%), pollakiuria (45.7%), UTI (42.9%), hematuria (31.4%), nocturia (31.4%), and hydronephrosis (17.1%).
  • TEAE treatment-emergent adverse event
  • An AE is considered ‘serious’ if, in the view of either investigator or sponsor, it results in any of the following outcomes: death, life-threatening experience, inpatient hospitalization, disability, a congenital anomaly or birth defect, or considered an important medical event.
  • a treatment-emergent adverse event is defined as an event that emerges, or a pre-existing event that worsens, any time after initiation of the first TAR-200 insertion procedure (Study Day 0 [Cycle 1 Day 0]) to the final Safety Maintenance Period follow-Up Visit.
  • Treatment-emergent AEs considered related to TAR-200 are summarized in Table 19. Overall, 15 (42.9%) subjects had at least 1 TEAE that was considered related to TAR-200. The TEAEs that were considered to be related to TAR-200 in >1 subject were dysuria (7 subjects [20.0%]), pollakiuria (5 subjects [14.3%]), nocturia, and urethral syndrome (3 subjects [8.6%] each).
  • a treatment- emergent adverse event is defined as an event that emerges, or a pre-existing event that worsens, any time after initiation of the first TAR-200 insertion procedure (Study Day 0 [Cycle 1 Day 0]) to the final Safety Maintenance Period follow-Up Visit.
  • TEAEs by Relationship to the Procedure (Urinary Placement Catheter or cystoscopy): Treatment-emergent AEs considered related to the procedure are summarized in Table 20. Overall, 9 subjects (25.7%) had at least 1 TEAE that was considered related to the procedure. The TEAEs that were considered to be related to the procedure in >1 subject were dysuria and UTI (2 subjects [5.7%] each).
  • Table 20 Number (%) of Subjects with Procedure Related Treatment-Emergent Adverse Events by SOC and Preferred Term -Safety Analysis Set
  • a treatment-emergent adverse event is defined as an event that emerges, or a preexisting event that worsens, any MedDRA Dictionary Version 24.1 is used for time after initiation of the first TAR-200 insertion procedure (Study Day 0 [Cycle 1 Day 0]) to the final Safety Maintenance Period follow-Up Visit.
  • Tolerability was defined as being tolerant of TAR-200 indwelling for the designated period of time and not requiring TAR-200 removal prior to the scheduled date of removal due to meeting any of the Subject Stopping Safety Criteria or other drug or device constituent related AE.
  • the proportion of subjects who were tolerant/not tolerant during each dosing cycle and at any time during the study is summarized in Table 21. Two subjects (5.7%) did not meet the protocol-specified tolerability criteria. Both subjects had TAR-200 removed early due to TEAEs, one subject had the TAR-200 removed early after 16 days during Cycle 1 and the other after 15 days during Cycle 4.
  • Tolerability is defined as being tolerant of TAR-200 indwelling for the designated period of time and does not require TAR-200 removal prior to the scheduled date of removal due to meeting any of the Subject Stopping Safety Criteria or other drug or device constituent related AE.
  • the patient population enrolled in this study represented an elderly (median age 84 years) and frail group of subjects, with a large proportion showing high disability (ECOG) scores and significant ongoing comorbidities at study entry.
  • Pathological staging at diagnosis was T2 for 27 subjects, T2a for 4 subjects, and T2b for 4 subjects.
  • Safety and tolerability were evaluated throughout the induction and maintenance periods through to the Final Safety Follow-up Visit, which was scheduled to occur approximately 14 months after Study Day 0. Over this period, 34 of the 35 subjects (97.1%) in the Safety Analysis Set experienced at least 1 TEAE.
  • the most common TEAEs were dysuria, pollakiuria, UTI, hematuria, nocturia and hydronephrosis. These types of events were not unanticipated in this patient population considering the underlying disease state. Renal and urinary disorders were also commonly reported as medical history findings prior to initiation of TAR-200 dosing.
  • Subjects could have their TAR-200 removed early (or have their TAR-200 insertion delayed) if they met certain tolerability criteria. Overall, TAR-200 was well tolerated and only 2 subjects 5.7%) did not meet the protocol-specified criteria of “tolerant”.
  • An assessment of clinical response was performed at the end of the induction period (Month 3) based on a composite evaluation of cystoscopic assessment of visual lesions, evaluation of metastases (based on CT, MRI, or PET scans), and pathologic staging of the bladder biopsy specimen. Of the 35 subjects enrolled in the study, 31.4% (11/35 subjects) had a CR and 8.6% (3/35 subjects) had a PR, yielding an overall response rate of 40.0% (14/35 subjects). Six subjects (17.1%) had stable disease and 6 (17.1%) had disease progression.
  • Subjects were permitted to receive procedural interventions for symptom palliation after the induction period. Ten subjects (28.6%) had received procedural intervention. The 25th percentile of the time to intervention (based on the Kaplan-Meier estimate) was 3.7 months; the median was not estimable.
  • the FACT-BL a patient-reported outcome (PRO) measure, was used to evaluate health- related quality of life (HRQoL).
  • the FACT-B1 total score ranges from 0-156, with higher scores indicating better HRQoL.
  • the median FACT-BL total score at baseline was 105.8 (range: 83.8 and 136.3).
  • the median FACT-BL total score was numerically higher at 117.4 (range: 74.8 and 134.0), suggesting overall maintenance of HRQoL.
  • Clinical response was evaluated at the end of the induction period (Month 3) following 4 consecutive 21-day TAR-200 dosing cycles.
  • 14 subjects (40%) had a response (31.4% had a CR and 8.6% had a PR).
  • the Kaplan-Meier estimated median duration of response in these 14 subjects was 14 months, and the estimated event-free rate (ie, proportion of subjects still in response) was 92.3% at 6 months, 70.5% at 12 months, 28.2% at 18 months and 14.1% at 24 months.

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Abstract

La présente invention concerne des méthodes, des systèmes, des articles manufacturés et des kits associés au traitement du cancer de la vessie invasif musculaire avec de la gemcitabine.
PCT/US2023/077958 2022-10-28 2023-10-26 Méthodes de traitement du cancer de la vessie avec de la gemcitabine WO2024092159A1 (fr)

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