Study of Bacillus Calmette-Guerin (BCG) Combined With PANVAC Versus BCG Alone in Adults With High Grade Non-Muscle Invasive Bladder Cancer Who Failed At Least 1 Course of BCG

Background: * High grade (G3) non-muscle invasive urothelial carcinoma of the bladder (stages Ta, T1, and carcinoma in situ (CIS) has a high rate of recurrence and progression * The standard of care therapeutic agent is a single induction course of bacillus Calmette- Guerin (BCG) * Although a second induction course can be used in patients who fail a single induction course of BCG, only 35% of patients who failed an initial induction course will experience 12 month disease-free survival after receiving a second induction course * For those patients failing a second induction course, radical cystectomy with pelvic lymphadenectomy is the recommended treatment, although it has a high morbidity rate and a small but real mortality rate * Therefore, there is an unmet need for localized treatment for patients who fail an initial induction course of BCG that can potentially improve upon the poor results of a second induction course of BCG * Recently, a unique pox viral vector-based vaccine, PANVAC, has been shown to induce a cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) antigen-specific immune response against the tumor-associated antigens (TAAs), carcinoembryonic antigen (CEA) and mucin-1 (MUC-1). This vaccine also contains transgenes for three human T cell co-stimulatory molecules that can potentially augment an immune response * We hypothesize that the combined administration of BCG and PANVAC may augment the BCG-induced cytotoxic T lymphocyte response against bladder cancer cells expressing MUC-1 and/or CEA and potentially reverse BCG failure in patients that have failed one induction course of BCG Objectives: -To determine if there is an improvement in disease-free survival (DFS) with BCG + PANVAC compared with BCG alone in a phase II study in non-muscle invasive high-grade urothelial carcinoma of the bladder who have failed to respond to intravesical BCG within 1 year post treatment. Eligibility: * Individuals who have failed at least one previous induction course of intravesical BCG, defined as histologically confirmed persistent or relapsing tumor present on post-BCG endoscopic evaluation. All BCG failures will be considered for inclusion into the study, including BCG-refractory,-resistant, and -relapsing, as defined in the Rationale and Background. For the purposes of the study, BCG-refractory and BCG-resistant subjects will be considered to have BCG-persistent disease. * Patients who are not currently candidates for radical cystectomy (e.g. patient refuses surgery, comorbidities preclude major surgery, etc.). * Normal organ function, Eastern Cooperative Oncology Group (ECOG) 0-2. Design: * This is a randomized, open label prospective, Phase II study in subjects with non-muscle invasive high grade urothelial carcinoma of the bladder who have failed at least one induction course of intravesical BCG, randomized to one of the following arms: BCG intravesical live (TICE BCG) +PANVAC or TICE BCG alone. Randomization is stratified by BCG treatment subgroup. * All subjects will receive intravesical TICE BCG (50mg) as per usual standard of care once weekly starting in week 3 for a total of 6 weeks. * The combination arm will receive the pox viral vaccines that contain the transgenes for CEA and MUC-1 (both with modified human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2) agonist epitopes) as well as 3 human T-cell costimulatory molecules, B7-1, intercellular adhesion molecule (ICAM-1), and lymphocyte function associated antigen 3 (LFA-3) \[rV-PANVAC (vaccinia) and rFPANVAC (fowlpox)\] as follows: * rV-PANVAC 2 x 10(8) pfu subcutaneous (SQ) at week 0 only. * rF-PANVAC1 x 10(9) pfu SQ at weeks 3, 7, 11, and 15. * For this Phase II study, we will test the hypothesis that subjects in the TICE BCG +PANVAC arm have better disease-free survival than subjects in the TICE BCG alone arm. * Patient accrual is targeted at one patient per month during the first 6 months and 1-2 patients per 1-2 months afterwards, and follow-up period after completing accrual will be 12 months post treatment. * Based on a power of 84% and type 1 error (1-sided) of 0.15, a total of 49 subjects will need to be accrued. * Allowing for a proportion of the subjects not being evaluable, a maximum of 54 subjects will be accrued.