Different Versions of BCG with or without Vaccine Therapy in Treating Patients with High Grade Bladder Cancer That Is Not Muscle Invasive
This randomized phase III trial studies bacillus Calmette-Guerin (BCG) Tokyo-172 strain solution with or without a vaccination, BCG Tokyo-172 strain vaccine, to see how well it works compared with BCG solution in treating patients with bladder cancer that has not spread to muscle. BCG is a weakened form of the bacterium Mycobacterium bovis that does not cause disease. BCG is used in a solution to stimulate the immune system in the treatment of bladder cancer. Giving different versions of BCG with vaccine therapy may prevent bladder cancer from returning.
Inclusion Criteria
- Patients must have histologically proven Ta, carcinoma in situ (CIS) or T1 stage urothelial cell carcinoma of the bladder within 90 days prior to 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 nodal involvement or metastatic disease (MRI or 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
- No other prior non-bladder 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 or intradermal BCG
- 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
- Patients must not have known history of tuberculosis
- Patients must be negative for prior Tuberculosis infection as determined by a negative PPD test; if PPD is not available, then a negative interferon gamma release assay (IGRA) may be used; the PPD or IGRA test results must be obtained 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); for PPD readings done outside of 48-72 hour window, patients must have PPD test and reading repeated to confirm eligibility; IGRA positive is defined by the laboratory interpretation or using the package insert cut-off values; any IGRA approved by the Food and Drug Administration (FDA) is allowed, including the QuantiFERON®–tuberculosis (TB) Gold In-Tube test (QFT–GIT) or the T–SPOT® TB test (T–Spot)
- Patients must be >= 18 years of age
- Prestudy history and physical must be obtained within 90 days prior to registration; patients must have a complete blood count (CBC) and basic metabolic panel including creatinine, potassium, chloride, blood urea nitrogen (BUN), carbon dioxide (CO2) and glucose within 28 days prior to registration
- Patients must not be pregnant or nursing as the use of intravesical BCG is not recommended during pregnancy; 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
- Patients who can complete patient-reported outcome (PRO) forms in English or Spanish must complete the baseline Bladder Cancer Index, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core (C) 30, American Urological Association Symptom Score (AUASS), and Cancer Patient Tobacco Use Questionnaire forms
Additional locations may be listed on ClinicalTrials.gov for NCT03091660.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To compare whether time to high-grade recurrence (TTHGR) for patients with BCG-naive, non-muscle invasive bladder cancer (NMIBC) receiving BCG Tokyo-172 strain solution (Tokyo-172 BCG) (Arm 2) is non-inferior to patients receiving BCG solution (BCG LIVE [TICE BCG]) (Arm 1).
II. To test whether TTHGR for patients with BCG-naive, NMIBC receiving intradermal BCG Tokyo-172 strain vaccine (Tokyo-172 BCG vaccination) followed by intravesical Tokyo-172 BCG instillation (Arm 3) is superior to patients receiving intravesical Tokyo-172 BCG instillation without prior intradermal BCG vaccination (Arm 2).
SECONDARY OBJECTIVES:
I. To compare time to recurrence (TTR) with any-grade (AG) bladder cancer between:
Ia. patients receiving Tokyo-172 versus BCG LIVE (TICE BCG) strain.
Ia. Patients receiving intradermal + intravesical versus intravesical only Tokyo-172 BCG.
II. To compare progression-free survival (PFS) between:
IIa. Patients receiving Tokyo-172 versus BCG LIVE (TICE BCG) strain.
IIa. Patients receiving intradermal + intravesical versus intravesical only Tokyo-172 BCG.
III. To estimate the complete response (CR) rate for carcinoma in situ (CIS) patients at 6 months in patients receiving intravesical versus intravesical only Tokyo-172 BCG (Arms 2 & 3 will be evaluated separately).
IV. To evaluate the duration of CR by treatment arm for patients with CIS who have a CR at 6 months.
V. To test whether TTHGR for patients with BCG-naive, NMIBC receiving intradermal Tokyo-172 BCG vaccination followed by intravesical Tokyo-172 BCG instillation is superior to patients receiving intravesical TICE BCG strain.
PRIMARY TRANSLATIONAL RESEARCH 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 measured prior to weeks 1, 3 and 6 BCG instillation 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.
IV. To assess whether changes in pre-BCG extracellular vesicle profiles in urine and blood from week 1 to week 3 vary by treatment arm and whether these changes are prognostic for TTHGR.
PATIENT REPORTED OUTCOMES OBJECTIVES:
I. To compare the change (baseline to 6 month) in patient-reported bladder cancer-specific quality of life between TICE and Tokyo BCG strains.
II. To compare the change (baseline to 6 month) in patient-reported quality of life between priming and no priming.
III. To test the hypothesis that changes in urinary symptoms during BCG treatment predict time to high-grade recurrence (TTHGR).
IV. To evaluate whether smoking status is associated with time TTHGR, and whether the efficacy of BCG strain (Tice versus [vs.] Tokyo) and BCG priming is modified by measures of smoking exposure.
V. To estimate adverse event profiles for each of the three treatment arms by smoking status.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM 1:
INDUCTION: Patients receive BCG solution intravesically once a week for 6 weeks in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive BCG solution intravesically once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 21 doses in the absence of disease progression or unacceptable toxicity.
ARM 2:
INDUCTION: Patients receive BCG Tokyo-172 strain solution intravesically once a week for 6 weeks in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive BCG Tokyo-172 strain solution intravesically once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 21 doses in the absence of disease progression or unacceptable toxicity.
ARM 3:
PRIME: Patients receive BCG Tokyo-172 strain vaccine once intradermally (ID) in the absence of disease progression or unacceptable toxicity.
INDUCTION: Within 21 days, patients receive BCG Tokyo-172 strain solution as in Arm 2.
MAINTENANCE: Patients receive BCG Tokyo-172 strain solution as in Arm 2.
All patients undergo magnetic resonance imaging (MRI) or computed tomography (CT), as well as CT urography, MRI urography or intravenous pyelography during screening. Patients also undergo cystoscopy and blood sample collection during screening and on the trial and may undergo biopsies on the trial.
After completion of study treatment, patients are followed up for 5 years.
Trial PhasePhase III
Trial Typetreatment
Lead OrganizationSWOG
Principal InvestigatorRobert Scott Svatek
- Primary IDS1602
- Secondary IDsNCI-2016-00451
- ClinicalTrials.gov IDNCT03091660