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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Stage 0 Bladder Urothelial Carcinoma, Stage 0is Bladder Urothelial Carcinoma, Stage I Bladder Urothelial Carcinoma

Intervention / Treatment
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* Biological: BCG Solution
* Biological: BCG Tokyo-172 Strain Solution
* Biological: BCG Tokyo-172 Strain Vaccine
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically proven Ta, carcinoma in situ (CIS) or T1 stage urothelial cell carcinoma of the bladder within 90 days of registration Patients must have had all grossly visible papillary tumors removed within 30 days prior to registration or cystoscopy confirming no grossly visible papillary tumors within 30 days prior to registration Patients with T1 disease must have cross-sectional imaging of abdomen/pelvis demonstrating no evidence of metastatic disease (magnetic resonance imaging [MRI] or computed tomography [CT] scan) within 90 days prior to registration; patients with T1 disease must have re-resection confirming =< T1 disease within 90 days prior to registration Patients must have high-grade bladder cancer as defined by 2004 World Health Organization (WHO)/International Society of Urological Pathology (ISUP) classification Patients must not have pure squamous cell carcinoma or adenocarcinoma Patients' disease must not have micropapillary components Patients must have no evidence of upper tract (renal pelvis or ureters) cancer confirmed by one of the following tests performed within 90 days prior to registration: CT urogram, intravenous pyelogram, magnetic resonance (MR) urogram, or retrograde pyelograms Patients must not have nodal involvement or metastatic disease No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years; patients with localized prostate cancer who are being followed by an active surveillance program are also eligible Patients must have a Zubrod performance status of 0-2 Patients must not have received prior intravesical BCG Patients must not have known history of tuberculosis Patients must be PPD negative within 90 days prior to registration; PPD negativity is defined as < 10 mm diameter induration (palpable, raised hardened area) in the volar forearm at 48-72 hours following injection with standard tuberculin dose (5 units, 0.1 ml) Patients must be >= 18 years of age Patients must not be taking oral glucocorticoids at the time of registration Patients must not be planning to receive concomitant biologic therapy, hormonal therapy, chemotherapy, surgery, or other cancer therapy while on study Prestudy history and physical must be obtained within 90days prior to registration Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures Patients must be offered the opportunity to participate in specimen banking for future studies to include translational medicine studies
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (BCG solution)<br>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. | Biological: BCG Solution<br>* Given intravesically<br>* Other names: TICE BCG Solution;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II (Tokyo-172 strain BCG solution)<br>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. | Biological: BCG Tokyo-172 Strain Solution<br>* Given intravesically<br>* Other names: Immunobladder;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm III (Tokyo-172 strain BCG solution with priming)<br>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. | Biological: BCG Tokyo-172 Strain Solution<br>* Given intravesically<br>* Other names: Immunobladder;Biological: BCG Tokyo-172 Strain Vaccine<br>* Given ID<br>* Other names: Bacillus Calmette-Guerin Tokyo-172 Strain Vaccine;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TTHGR for Arm I compared to Arm II | Time to High Grade Recurrence | Time from randomization to first high grade recurrence assessed up to 5 years | 
| TTHGR for Arm II compared to Arm III | Time to High Grade Recurrence | Time from randomization to first high grade recurrence assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free rates | Rates of patients who are disease free at six months versus not | At 6 months |