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Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Non-Muscle Invasive Bladder Neoplasms

Neoplasms, Glandular and Epithelial

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Female Urogenital Diseases and Pregnancy Complications

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Pharmaceutical Solutions

Pembrolizumab

BCG Vaccine

Vaccines

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Adjuvants, Immunologic

Immunologic Factors

PRE-INDUCTION PHASE: Patients receive pembrolizumab intravesically once on day -14.

INDUCTION PHASE: Patients receive BCG solution intravesically once weekly for 6 weeks at weeks 0-5 and pembrolizumab intravesically every 2 weeks at weeks 0, 2, and 4.

MAINTENANCE PHASE: Beginning 2 weeks after the last dose of BCG solution, patients receive pembrolizumab intravesically every 2 weeks for 12 weeks at weeks 7, 9, 11, 13, 15, and 17 for a total of 6 doses. Patients then receive pembrolizumab intravesically every 4 weeks at weeks 21, 25, 29, 33, 37, 41, 45, and 49 for a total of 8 doses.

BCG Solution

Laboratory Biomarker Analysis

Pharmacological Study

Joshua Meeks

The purpose of this study is to evaluate the efficacy (the effect of drug on tumor) and the tolerability (the effect of drug on the body) of pembrolizumab, when given as a single agent in patients with bladder tumors. Another purpose of the study is to see what tumor characteristics are associated with increased efficacy of the pembrolizumab. Pembrolizumab (MK-3475) is an antibody (a human protein that sticks to a part of the tumor and/or immune cells) designed to allow the body's immune system to work against tumor cells. Pembrolizumab is Food and drug Administration (FDA) approved for the treatment of advanced melanoma (a type of skin cancer) and some types of lung cancer. It is not yet approved by the United States Food and Drug Administration (USFDA) for bladder cancer, hence it is considered an investigational agent for this disease.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the study drug (pembrolizumab \[MK-3475\]) when administered intravesically in combination with BCG in patients with high risk or BCG-refractory non-muscle-invasive bladder cancer (up to the individual maximum tolerated dose of each drug alone).

SECONDARY OBJECTIVES:

I. To describe the dose limiting toxicities (DLTs) of MK-3475 in combination with BCG in this population.

II. To assess the safety and tolerability of the combination of MK-3475 and BCG in subjects with high risk or BCG-refractory non-muscle-invasive bladder cancer.

TERTIARY OBJECTIVES:

I. To characterize the pharmacokinetics (PK) of MK-3475 in both blood and urine when administered intravesically in combination with BCG.

II. To measure humoral and cellular responses to tumor antigens on serum and urine samples by measuring the levels of cytokines (ie, interleukin \[IL\]-2, IL-6, IL-8, IL-10, IL-18, interferon gamma \[IFN-gamma\] and tumor necrosis factor alpha \[TNF-alpha\]) and peripheral blood lymphocyte phenotype throughout treatment.

III. To determine the response rate in terms of complete pathologic response in this population assessed when patient undergoes cystoscopies (weeks 17, 25, 33, 41, and 49 if applicable).

IV. To document the progression rate associated with the combination of intravesical MK-3475 and BCG in patients with high risk or BCG-refractory non-muscle-invasive bladder cancer.

V. To evaluate the relationship between tumor biomarkers programmed cell death (PD)-ligand (L)1, PD-L2, PD-1 as defined by immunohistochemistry (IHC) and adverse effects and recurrence rate.

OUTLINE: This is a dose-escalation study of pembrolizumab.

PRE-INDUCTION PHASE: Patients receive pembrolizumab intravesically once on day -14.

INDUCTION PHASE: Patients receive BCG solution intravesically once weekly for 6 weeks at weeks 0-5 and pembrolizumab intravesically every 2 weeks at weeks 0, 2, and 4.

MAINTENANCE PHASE: Beginning 2 weeks after the last dose of BCG solution, patients receive pembrolizumab intravesically every 2 weeks for 12 weeks at weeks 7, 9, 11, 13, 15, and 17 for a total of 6 doses. Patients then receive pembrolizumab intravesically every 4 weeks at weeks 21, 25, 29, 33, 37, 41, 45, and 49 for a total of 8 doses.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Pembrolizumab and BCG Solution in Treating Patients With Recurrent Non-Muscle-Invasive Bladder Cancer

A Phase 1 Dose-Escalation Study of Intravesical MK-3475 and Bacillus Calmette-Guerin (BCG) in Subjects With High Risk and BCG-Refractory Non-Muscle-Invasive Bladder Cancer

Blood will be collected for measurement of cytokines in order to explore humoral and cellular responses to MK-3475 and BCG treatments. Cytokines will be measured using ELISA assays.

Urine will be collected for measurement of cytokines in order to explore humoral and cellular responses to MK-3475 and BCG treatments. Cytokines will be measured using ELISA assays.

Expression of tumor biomarker PD-L1 as defined by immunohistochemistry (IHC) will be assessed and results will be correlated with adverse effects and recurrence rate. This evaluation will be performed on archived tissue samples obtained at baseline and on fresh tissue from any subsequent biopsies.

Expression of tumor biomarker PD-1 as defined by immunohistochemistry (IHC) will be assessed and results will be correlated with adverse effects and recurrence rate. This evaluation will be performed on archived tissue samples obtained at baseline and on fresh tissue from any subsequent biopsies.

Expression of tumor biomarker PD-L2 and immune cell infiltration as defined by immunohistochemistry (IHC) will be assessed and results will be correlated with adverse effects and recurrence rate. This evaluation will be performed on archived tissue samples obtained at baseline and on fresh tissue from any subsequent biopsies.

Peripheral blood will be taken for evaluation of a lymphocyte profile which will be analyzed using automated flow cytometric techniques and will measure humoral and cellular response to tumor antigens.

Blood serum concentrations of MK-3475 will be evaluated during pre-induction (week -2) at baseline (0 minutes) and at 15, 30, and 60 minutes post-dosing for determination of plasma PK parameters.

Blood serum concentrations of MK-3475 will be evaluated during induction (week 4) at baseline (0 minutes) and at 15, 30, and 60 minutes post-dosing for determination of plasma PK parameters.

Urine concentrations of MK-3475 will be evaluated during induction (week -2) at 30 minutes prior to dosing and 2 hours post-dosing for determination of urine concentration-time profile.

Urine concentrations of MK-3475 will be evaluated during induction (week 4) at 30 minutes prior to dosing and 2 hours post-dosing for determination of urine concentration-time profile.

Determine the response rate in terms of complete pathologic response in this population will be assessed when the patient undergoes cystoscopies. Patients will be examined via bladder cystoscopy and may undergo biopsy for pathological confirmation if needed. Responses will be categorized as yes or no for bladder recurrence.

The progression rate of the tumor will be defined as positive transurethral resection and/or biopsy.

Determine the MTD of the study drug (MK-3475) when administered intravesically in combination with BCG in patients with high risk or BCG-refractory non-muscle-invasive bladder cancer (up to the individual maximum tolerated dose of each drug alone). The MTD will be defined as the highest dose that causes dose limiting toxicities (DLTs) in \<2 of 6 patients graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Evaluate the DLTs of MK-3475 in combination with BCG in this population. DLTs will be defined as significant adverse events occurring during the DLT observation period (2 week pre-induction phase and the 7 weeks of induction phase) that is related to either drug or the combination. DLT will be evaluated according to CTCAE v 4.03 criteria.

Determine the safety and tolerability of the combination of MK-3475 and BCG in subjects with high risk or BCG-refractory non-muscle-invasive bladder cancer by evaluating the number, frequency, and severity of adverse events using CTCAE v 4.03. This table provides the number of patients with their worst grade toxicity for any AEs a patient experienced and AEs that were found to have a possible, probable, or definite attribution with at least one of the study treatment agents.

Merck Sharp & Dohme LLC

National Cancer Institute (NCI)

Northwestern University

Joshua Meeks, MD, PhD

PRE-INDUCTION PHASE: Patients receive pembrolizumab intravesically once on day -14.

INDUCTION PHASE: Patients receive BCG solution intravesically once weekly for 6 weeks at weeks 0-5 and pembrolizumab intravesically every 2 weeks at weeks 0, 2, and 4.

MAINTENANCE PHASE: Beginning 2 weeks after the last dose of BCG solution, patients receive pembrolizumab intravesically every 2 weeks for 12 weeks at weeks 7, 9, 11, 13, 15, and 17 for a total of 6 doses. Patients then receive pembrolizumab intravesically every 4 weeks at weeks 21, 25, 29, 33, 37, 41, 45, and 49 for a total of 8 doses.

BCG Solution: Given intravesically

Laboratory Biomarker Analysis: Correlative studies

Pembrolizumab: Given intravesically

Pharmacological Study: Correlative studies

Phase I: Cohort 1 (1 mg/kg Pembrolizumab, 50 mg BGC)

Phase I: Cohort 2 (2 mg/kg Pembrolizumab, 50 mg BGC)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

The TNM staging system is the common language in which oncology health professionals can communicate on the cancer extent for individual patients as a basis for decision making on treatment management and individual prognosis but can also be used, to inform and evaluate treatment guidelines. Tumors confined to the mucosa and invading the lamina propria are classified as stage Ta and T1, respectively, according to the Tumour, Node, Metastasis (TNM) classification system. Intra-epithelial, high-grade (HG) tumors confined to the mucosa are classified as CIS (Tis).

Cancer Stage at Baseline

PRE-INDUCTION PHASE: Patients receive pembrolizumab intravesically once on day -14.

INDUCTION PHASE: Patients receive BCG solution intravesically once weekly for 6 weeks at weeks 0-5 and pembrolizumab intravesically every 2 weeks at weeks 0, 2, and 4.

MAINTENANCE PHASE: Beginning 2 weeks after the last dose of BCG solution, patients receive pembrolizumab intravesically every 2 weeks for 12 weeks at weeks 7, 9, 11, 13, 15, and 17 for a total of 6 doses. Patients then receive pembrolizumab intravesically every 4 weeks at weeks 21, 25, 29, 33, 37, 41, 45, and 49 for a total of 8 doses.

BCG Solution: Given intravesically Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given intravesically Pharmacological Study: Correlative studies

Phase I: Cohort 1 (1 mg/kg Pembrolizumab, 50 mg BGC) & Cohort 2 (2 mg/kg Pembrolizumab, 50 mg BGC)

Maximum Tolerated Dose (MTD)

Dose Limiting Toxicities (DLTs)

All Adverse Events Grades 1-2

All Adverse Events Grade 3

All Averse Events Grade 5

Pembrolizumab Attributed Adverse Events Only Grade 1-2

Pembrolizumab Attributed Adverse Events Only Grade 5

BGC Attributed Adverse Events Only Grade 1-2

Cohort 2 (2 mg/kg Pembrolizumab, 50 mg BGC)

Incidence of Adverse Events

Change in Cytokines in the Blood

Change in Cytokines in Urine

Expression of PD-L1

Expression of PD-1

Expression of PD-L2

Lymphocyte Profile

Plasma Concentration-time Profile

Urine Concentration-time Profile

Response Rate

Tumor Progression

Phase I: Cohort 2 (2 mg/kg Pembrolizumab, 50 mg BCG)

Pre-Induction Period

Induction Period

Maintenance Phase

Survival Follow-Up

INDUCTION: Patients receive TICE BCG solution intravesically once a week for 6 weeks. MAINTENANCE: Patients receive TICE BCG solution once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 7 doses.

INDUCTION: Patients receive Tokyo-172 strain BCG solution intravesically once a week for 6 weeks. MAINTENANCE: Patients receive Tokyo-172 strain BCG solution once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 7 doses.

PRIME: Patients receive Tokyo-172 strain BCG vaccine once ID. INDUCTION: Within 21 days, patients receive Tokyo-172 strain BCG solution as in Arm II. MAINTENANCE: Patients receive Tokyo-172 strain BCG solution as in Arm II.

BCG Tokyo-172 Strain Solution

BCG Tokyo-172 Strain Vaccine

Robert Svatek

This randomized phase III trial studies Tokyo-172 strain bacillus Calmette-Guerin (BCG) solution with or without a vaccination using Tokyo-172 strain BCG to see how well it works compared with TICE BCG solution in treating patients with bladder cancer that has not spread to muscle. BCG is a non-infectious bacteria that when instilled into the bladder may stimulate the immune system to fight bladder cancer. Giving different versions of BCG with vaccine therapy may prevent bladder cancer from returning.

PRIMARY OBJECTIVES:

I. To compare whether time to high grade recurrence (TTHGR) for patients with BCG-naïve, non-muscle invasive bladder cancer (NMIBC) receiving Tokyo-172 BCG strain (Arm II) is non-inferior to patients receiving TICE BCG strain (Arm I).

II. To test whether TTHGR for patients with BCG-naïve, NMIBC receiving intradermal Tokyo-172 BCG vaccination followed by intravesical Tokyo-172 BCG instillation (Arm III) is superior to patients receiving intravesical Tokyo-172BCG instillation without prior intradermal BCG vaccination (Arm II).

SECONDARY OBJECTIVES:

I. To compare time to recurrence (TTR) with any-grade (AG) bladder cancer between patients receiving Tokyo-172 versus TICE BCG strain.

II. To compare TTR with AG bladder cancer between patients receiving intradermal + intravesical versus intravesical only Tokyo-172 BCG.

III. To compare progression-free survival (PFS) between patients receiving Tokyo-172 versus TICE BCG strain.

IV. To compare PFS between patients receiving intradermal + intravesical versus intravesical only Tokyo-172 BCG.

V. To compare 6-month complete response in patients with carcinoma in situ (CIS) with or without Ta or T1 cancer present at baseline receiving Tokyo-172 versus TICE BCG strain.

VI. To compare 6-month complete response in patients with CIS with or without Ta or T1 cancer present at baseline receiving intradermal + intravesical versus intravesical only Tokyo-172 BCG.

TERTIARY OBJECTIVES:

I. To test the hypothesis that purified protein derivative (PPD) test conversion (positive PPD at 3 or 6 months) following BCG immunotherapy will predict time to high grade recurrence (TTHGR).

II. To test the hypothesis that urinary cytokine levels following BCG immunotherapy will predict time to high grade recurrence (TTHGR).

III. To test the hypothesis that tumor neoantigen burden and T lymphocyte infiltration are associated with BCG response.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I:

INDUCTION: Patients receive TICE BCG solution intravesically once a week for 6 weeks.

MAINTENANCE: Patients receive TICE BCG solution once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 7 doses.

ARM II:

INDUCTION: Patients receive Tokyo-172 strain BCG solution intravesically once a week for 6 weeks.

MAINTENANCE: Patients receive Tokyo-172 strain BCG solution once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 7 doses.

ARM III:

PRIME: Patients receive Tokyo-172 strain BCG vaccine once intradermally (ID).

INDUCTION: Within 21 days, patients receive Tokyo-172 strain BCG solution as in Arm II.

MAINTENANCE: Patients receive Tokyo-172 strain BCG solution as in Arm II.

After completion of study treatment, patients are followed up for 5 years.

S1602: Different Strains of BCG With or Without Vaccine in High Grade Non- Muscle Invasive Bladder Cancer

S1602, A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming With Intradermal BCG Before Intravesical Therapy for BCG-Naive High-Grade Non-muscle Invasive Bladder Cancer

https://swog.org/Visitors/Download/Policies/Policy43.pdf

Rates of patients who are disease free at six months versus not

SWOG Cancer Research Network

Questionnaire Administration

Radical Cystectomy

Mihir Desai

This randomized phase II trial studies how well robotic radical cystectomy (RRC) or open radical cystectomy (ORC) works in treating patients with bladder cancer. Cystectomy is a surgical procedure to remove all or part of the bladder (the organ that holds urine) or to remove a cyst (a sac or capsule in the body). In RRC, the the surgeon makes small cuts in the abdomen and uses a thin, lighted instrument with a camera attached called a scope. With the help of a robot, the surgeon removes the bladder and other nearby structures. In ORC, the surgeon makes a cut into the lower abdomen to expose the urinary tract in order to remove the bladder and nearby structures. It is not yet known whether RRC or ORC has fewer complications, better quality of life, and faster recovery time in treating patients with bladder cancer.

PRIMARY OBJECTIVES:

I. To compare RRC to ORC in terms of the difference in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core (QLQC)30 quality of life instrument assessed at baseline to day 30 after radical cystectomy (RC).

II. To compare RRC to ORC in terms of the 90-day high-grade complication rate (where high grade is defined as Clavien-Dindo grade 3-5).

III. To compare the peri-operative cost of the RC procedure, as defined as from the day of hospital admission to the day of hospital discharge.

SECONDARY OBJECTIVES:

I. To estimate the differences between RRC and ORC in terms of the following quality of life outcomes: Narcotic requirements prior to RC, during hospital stay and on days 7, 14, 30, 6 weeks, and 3, 6, 9 and 12 months; Visual Analog Scale (VAS) pain score prior to RC and on days 7, 14, 30, 6 weeks, and 3, 6, 9 and 12 months; the EORTC-QLQ-30 prior to RC and at 3, 6, 9, and 12 months; the bladder cancer index (BCI) at 30 days and 3, 6, 9, and 12 months; the Sexual Health Inventory for Men (SHIM) prior to RC and at 3, 6, 9, and 12 months; the World Health Organization (WHO) Quality of Life (QOL) questionnaire prior to RC and at 30 days and 3, 6, 9, and 12 months.

II. To estimate the differences between RRC and ORC in terms of the following surgical and complication outcomes: all complications occurring intraoperatively, during postoperative hospitalization and during the 90 days post cystectomy assessed at 7, 14, and 30 days; at 6 weeks and at 3 months-graded according to the Clavien-Dindo classification; all complications, all grade 3+ complications, and all grade 4+ complications; time to oral intake; estimated blood loss during surgery, number of transfusions on the day of surgery; drop in hematocrit at 24 hours; lymph node yield; and positive surgical margin.

III. To estimate the differences between RRC and ORC in terms of the following cost-related outcomes: operation room time; number of disposables used; pharmacy costs; length of hospital stay; admission to intensive care unit (ICU) prior to discharge \& length of stay in ICU; number of hospital readmissions within 30 and 90 days (3 months); necessary tests/procedures to treat complications during hospitalization and within 30 and 90 days.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo RRC at day 0.

ARM II: Patients undergo ORC at day 0.

After completion of study treatment, patients are followed up at 7 days, 30 days, 6 weeks, and at 3, 6, 9, and 12 months.

Robotic or Open Radical Cystectomy in Treating Patients With Bladder Cancer

Prospective Randomized Comparison of Robotic Versus Open Radical Cystectomy

The results for the two arms will be summarized using graphical methods and standard descriptive statistics. Means (or medians) and associated 95% confidence intervals-for each arm separately and for the difference-will be used to display the patterns. For QoL variables that are assessed at multiple times post cystectomy, regression methods that accommodate repeated measures will be used to assess patterns over time. Analyses will compare the two arms using general linear regression models and stratifying for the four variables used for stratification prior to randomization.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab and BCG Solution in Treating Patients With Recurrent Non-Muscle-Invasive Bladder Cancer	NCT02808143	Recurrent Bladd... Stage 0a Bladde... Stage 0is Bladd... Stage I Bladder...	BCG Solution Laboratory Biom... Pembrolizumab Pharmacological...	18 Years -	Northwestern University
S1602: Different Strains of BCG With or Without Vaccine in High Grade Non- Muscle Invasive Bladder Cancer	NCT03091660	Stage 0 Bladder... Stage 0is Bladd... Stage I Bladder...	BCG Solution BCG Tokyo-172 S... BCG Tokyo-172 S... Laboratory Biom...	-	SWOG Cancer Research Network
Robotic or Open Radical Cystectomy in Treating Patients With Bladder Cancer	NCT02699853	Stage 0is Bladd... Stage I Bladder... Stage II Bladde... Stage III Bladd...	Questionnaire A... Radical Cystect... Radical Cystect...	-	University of Southern California
Pembrolizumab and BCG Solution in Treating Patients With Recurrent Non-Muscle-Invasive Bladder Cancer	NCT02808143	Recurrent Bladd... Stage 0a Bladde... Stage 0is Bladd... Stage I Bladder...	BCG Solution Laboratory Biom... Pembrolizumab Pharmacological...	18 Years -	Northwestern University

Spots Global Cancer Trial Database for stage 0is bladder urothelial carcinoma