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