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
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Many cancers produce two particular proteins. The immune system can target these to attack
      the cancer. The PANVAC vaccine puts genes for these proteins inside a virus vaccine so the
      body sees the proteins as foreign invaders and attacks them. Researchers will test PANVAC on
      people with high grade non-muscle invasive bladder cancer. They will give it to people who
      have not responded to the usual treatment, bacillus Calmette-Guerin (BCG) over several weeks.
      They want to see if PANVAC plus BCG is better than BCG alone.

      Objective:

      - To compare the effects of PANVAC plus BCG therapy, to BCG therapy alone.

      Eligibility:

      - Adults 18 and older with high grade non-muscle invasive bladder cancer who failed at least
      1 course of BCG.

      Design:

        -  Participants will be screened with blood and urine tests and abdominal scans.

        -  Participants will be randomly assigned to get BCG only or BCG plus PANVAC.

        -  They will have up to 10 visits over 15 weeks. Most of these are part of usual cancer
           care.

        -  They will have blood and urine tests.

        -  All participants will get BCG in 6 weekly injections.

        -  One group will also get PANVAC in 5 injections over 15 weeks.

        -  Between weeks 17 and 20, participants will undergo tests of the tumor area as part of
           their usual care. They will have cystoscopy, exam under anesthesia, and bladder biopsy.
           Results will be used to evaluate the different treatments.

        -  Participants will have quarterly follow-up visits for up to 2 years.
    

Detailed description: 
      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.
    

Intervention name(s): BCG intravesical live (TICE Bacillus Calmette-Guerin (BCG)); PANVAC
Intervention type(s): Biological; Biological
Intervention description(s): TICE BCG for intravesical use, is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis; A recombinant virus vector vaccine containing genes for human carcinoembryonic antigen (CEA), mucin-1 (MUC-1) and three co-stimulatory molecules (designated Triad of costimulatory molecules (TRICOM): B7.1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte function-associated antigen-3 (LFA-3).
Intervention MeSH terms: BCG Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Urothelial Carcinoma; Vaccines; Immunotherapy; TICE BCG; Intravesical Treatment