Durvalumab and Vicineum in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)

Phase 1

Completed

Conditions: Urinary Bladder Neoplasms

Interventions: Drug: Durvalumab
Drug: Vicineum
Drug: Acetaminophen
Drug: Antihistamine
Procedure: Bladder Biopsy
Procedure: TURBT
Procedure: Cystoscopy
Diagnostic Test: Urine cytology
Diagnostic Test: Electrocardiogram
Diagnostic Test: CT
Diagnostic Test: MRI

Registration Number: NCT03258593

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after treatment. The drugs Vicineum and Durvalumab may help the immune system find and destroy cancer cells.

Objective:

To test if the drugs Durvalumab and Vicineum together are safe and effective to treat people with bladder cancer that has not spread to the muscle in the bladder.

Eligibility:

People ages 18 and older who have bladder cancer that has not spread to the muscle in the bladder and was treated unsuccessfully with Bacillus Calmette-Guerin

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Tumor sample from previous surgery. If one is not available, they will have a biopsy: A small piece of tumor is removed.

Cystoscopy to examine the inside of the bladder. This may include a biopsy or removing tumors.

Computed tomography (CT) or magnetic resonance imaging (MRI): They lie in a machine that takes pictures of the body.

Electrocardiogram to test heart function

Participants will receive Durvalumab and Vicineum in 2 phases:

First phase: Durvalumab every 4 weeks and Vicineum once a week for 3 months

Second phase: Durvalumab every 4 weeks and Vicineum once every other week

Participants will have tumor samples taken every 3 months. They will have blood and urine tests throughout the study.

Participants will continue treatment for up to 2 years.

Participants will have a visit about 30 days after their last treatment. This includes blood and urine tests. It may include a cytoscopy or additional biopsies.

Detailed Description: In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390 deaths associated with bladder cancer. Bladder cancer is associated with the highest costs among all types of cancer, due to the need for lifelong routine monitoring and treatment. Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of high-grade disease, these therapies can become ineffective over time in up to two-thirds of patients and disease progression to muscle invasive bladder cancer (MIBC) can occur. In patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%. Progression to MIBC portends a poor outcome as only 50% of patients will survive five years despite undergoing radical cystectomy. Clearly, there is a large unmet need in therapeutic options for NMIBC that recurs or progresses.

Vicineum(TM) is a recombinant fusion protein, VB4-845, that contains a humanized single-chain antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on the surface of urothelial carcinoma cells and therefore represents a good target for Vicineum(TM) to bind to. In a previous phase II study in BCG refractory or BCG intolerant patients with high grade bladder cancer, 16% of patients treated with induction and maintenance therapy with Vicineum(TM) remained disease-free at 1 year. As a result, Vicineum(TM) is currently being evaluated as a single agent in a phase III trial.

Pre-clinical work with a drug called Proxinium, an earlier version of Vicineum(TM), demonstrated an abscopal effect and synergy with the use of a checkpoint blockade inhibitor. Although it was done in a non-small cell lung cancer (NSCLC) model, the results were impressive in causing tumor shrinkage. Durvalumab is a human monoclonal antibody (MAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 \[B7-H1\], cluster of differentiation \[CD\]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab has been demonstrated to have activity against advanced metastatic urothelial bladder cancer whose tumor has progressed during or after one standard platinum-based regimen in a phase I trial.

Therefore, this trial will take two agents with single agent activity against urothelial cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously Treated with BCG.

Objectives:

Primary Objectives:

To evaluate the safety and tolerability of durvalumab and Vicineum when administered in combination to subjects with BCG-refractory high-grade NMIBC

Eligibility:

Subjects must have a histologically confirmed high-grade non-muscle invasive urothelial carcinoma (transitional cell carcinoma) of the bladder as follows:

Carcinoma-in-situ (CIS) with or without papillary tumors

High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm eligibility, the timing of the last bladder biopsy to the initial dose of study treatment must be within 12 weeks.

Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the Food and Drug Administration (FDA): Subjects must have received at least two courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course). See exception below for persistent T1 disease below. There is no upper limit on the amount of prior BCG a subject may have received.

Patients with persistent T1 high grade disease on TURBT following a single induction course of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient is surgically unfit for cystectomy as deemed by the investigator or the patient declines cystectomy

Design:

This is a Phase I, open-label study of the combination of durvalumab and Vicineum in subjects with high-grade NMIBC previously treated with BCG.

All subjects will receive Vicineum intravesically and durvalumab systemically at the standard doses for both drugs as determined by Phase II trials for each drug, as no synergy or additive effect is expected for adverse events.

Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.

Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that patient is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.

Vicineum will be given as monotherapy for 1 week followed by treatment with the combination of Vicineum and durvalumab starting week 2.

In the initial six patients, three subjects at a time will enroll at these doses and schedules. Dose-liming toxicity (DLT) for each subject will be determined during the initial 6-week period that the subject is on treatment (i.e., the DLT period). When all subjects in the initial cohort have been on treatment through the DLT period, all available safety data will be considered in decisions to enroll additional subjects at this dose level, or to de-escalate the dose(s) of study drug(s), based on a standard "3 + 3" design. There will be no dose-escalations in this study. The dose of durvalumab will remain at 1500 mg every 4 weeks, and the dose of each intravesical Vicineum treatment can be reduced to 20 mg if the initial doses in combination induce DLTs.

After the first six patients, an additional 18 subjects will be enrolled at the initial doses or at the reduced doses (if DLTs resulted in the first 6 patients) in order to obtain additional safety data, biomarker data and preliminary anti-tumor activity.

Each subject's course will consist of the following periods:

Screening/Baseline Period: The subject is consented and undergoes screening assessments to determine eligibility for the study.

Treatment Period: The subject is treated and monitored for safety. Biomarker data will be obtained prior to treatment and at periodic intervals during treatment. Subjects who remain free of high-grade NMIBC after 12 months of study treatment may continue to receive treatment for an additional 12 months until they develop recurrent high-grade disease, disease progression, or intolerable toxicity, or meet another withdrawal criterion (e.g., consent withdrawal, pregnancy).

Post-Treatment. The subject will return to the study site monthly for up to 90 days after the last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing clinically significant related adverse events (AEs) or serious adverse events (SAEs) will have additional follow-up after the initial post-treatment visit.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Vicineum	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Antihistamine	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Bladder Biopsy	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	TURBT	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Cystoscopy	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Urine cytology	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Electrocardiogram	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	CT	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	MRI	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Vicineum	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Antihistamine	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Bladder Biopsy	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	TURBT	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Cystoscopy	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Urine cytology	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Electrocardiogram	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	CT	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	MRI	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Vicineum	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Antihistamine	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Bladder Biopsy	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	TURBT	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Cystoscopy	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Urine cytology	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Electrocardiogram	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	CT	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	MRI	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Vicineum	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Antihistamine	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Bladder Biopsy	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	TURBT	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Cystoscopy	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Urine cytology	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Electrocardiogram	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	CT	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	MRI	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Durvalumab	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Acetaminophen	Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Durvalumab	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg	Acetaminophen	Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Acetaminophen	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg	Durvalumab	Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Acetaminophen	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)
Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)	Durvalumab	Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)

Primary Outcome Measures

Name	Time	Method
Number of Grades 1-5 Adverse Events	Through study completion, an average of 315 days	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild, grade 2 is moderate, grade 3 is severe, grade 4 is life-threatening, and grade 5 is death related to adverse event.

Secondary Outcome Measures

Name	Time	Method
Urinary Epithelial Cell Adhesion Molecule (EpCAM) Compared Between Participants Who Have a Clinical Response to Therapy vs. Those Who do Not Respond	Baseline, week 1, weeks 2-5, week 6, week 10 and week 12	Urinary EpCAM will be measured and will be compared between participants who have a clinical response to therapy vs. those who do not respond. Although it is expected to have low power, a comparison of the EpCAM levels may be compared between the two response categories using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
Response Rate	From enrollment until event occurrence (recurrence, progression); twelve weeks.	The response to treatment will be determined for evaluable participants who receive treatment and was measured as follows: Recurrence is suspected and/or determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a transurethral resection of bladder tumor (TURBT). Complete response rate for carcinoma in situ (CIS) is defined as the absence of CIS upon follow-up biopsies. Disease progression is defined as upstaging from a lower stage to a higher stage (e.g., Ta to T1-T4 or T1 to T2-4; CIS to T1 or CIS to T2-T4; or any N+ or M+ in these high-grade tumors).
Pharmacokinetic Parameters in Urine Maximum Concentration (Cmax) of Vicineum	Baseline, week 1, week 6, week 12	Evaluate the pharmacokinetic parameters of Vicineum obtained by urine samples. Urinary Vicineum (in ng/mL).
Change in Programmed Death-ligand 1 (PD-L1) Levels Between Responders and Non-Responders	Baseline and after treatment with both agents, from enrollment up to 5 weeks	PD-L1 levels will be obtained at baseline and after treatment with both agents. The change in levels will be determined between the two measurements, and these changes will be compared between responders and non-responders. Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
Change in Programmed Cell Death Protein 1 (PD-1) Levels Between Responders and Non-Responders	baseline and after treatment with both agents	PD-1 levels will be obtained at baseline and after treatment with both agents. The change in levels will be determined between the two measurements, and these changes will be compared between responders and non-responders. Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
Change in Programmed Death-ligand 1 (PD-L1) Levels Between Participants Who Respond and Have Stable Disease (SD), and Those With Progressive Disease (PD)	Baseline and after treatment, from enrollment up to 5 weeks	PD-L1 levels will be obtained at baseline and after treatment with both agents. The change will be compared between those who respond or have stable disease (SD (clinical benefit=Complete Response (CR)+Partial Response (PR)+SD) and those with progressive disease (PD). Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
Change in Programmed Cell Death Protein 1(PD-1) Levels Between Participants Who Respond and Have Stable Disease (SD), and Those With Progressive Disease (PD)	baseline and after treatment	PD-1 levels will be obtained at baseline and after treatment with both agents. The change will be compared between those who respond or have stable disease (SD (clinical benefit=Complete Response (CR)+Partial Response (PR)+SD) and those with progressive disease (PD). Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
Changes in the Immune Parameters Obtained From Blood Samples	baseline, 3 weeks, and 5 weeks	All evaluable participants will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. Comparisons of the paired values will be performed using a Wilcoxon signed rank test, and a Hochberg adjustment may be used.
Changes in the Immune Parameters Obtained From Biopsies	baseline, 3 months, and 6 months	All evaluable participants will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from biopsies will be obtained from baseline vs. a single second biopsy at 6 months. Comparisons of the paired values will be performed using a Wilcoxon signed rank test, and a Hochberg adjustment may be used.
Disease Free Survival (DFS)	Assessed from start of therapy to disease recurrence or last follow up; up to 1 year.	A DFS curve will be created using the Kaplan-Meier method based on all participants considered to be evaluable based on having received protocol treatment. DFS survival is defined as the time from the start of treatment until disease recurrence or death. Recurrence is suspected and/or determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a bladder biopsy or transurethral resection of bladder tumor (TURBT).