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
Intervention: BCG intravesical live (TICE Bacillus Calmette-Guerin (BCG)); PANVAC
Intervention description: 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
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Urothelial Carcinoma; Vaccines; Immunotherapy; TICE BCG; Intravesical Treatment

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        3.1.1.1 Patients must have histologically confirmed localized high grade (G3) transitional
        cell carcinoma (urothelial carcinoma) of the bladder that is stage Ta, T1, and/or carcinoma
        in-situ (CIS) confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) 45
        days prior to study entry. This can be obtained at an outside hospital prior to entry into
        the study or at the NCI. However, all outside pathology specimens will require that the
        formalin-fixed paraffin embedded tissues be re-read by the Laboratory of Pathology, NCI.
        For patients enrolled at collaborating trial sites, diagnosis must be confirmed by the
        Department of Pathology at the institution where the patient is enrolled on the trial.

        Pathology can also be reviewed by the Laboratory of Pathology at the NCI if the
        participating trial site prefers another pathologic evaluation.

        3.1.1.2 Patients have failed at least one previous induction course of intravesical
        Bacillus Calmette-Guerin (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.

        3.1.1.3 Patients who are not currently candidates for radical cystectomy (e.g. patient
        refuses surgery, comorbidities preclude major surgery, etc.).

        3.1.1.4 Age >18 years.

        --Because no dosing or adverse event data are currently available on the use of BCG in
        combination with PANVAC in patients <18 years of age, children are excluded from this
        study.

        3.1.1.5 Eastern Cooperative Oncology Group (ECOG) performance status <2.

        3.1.1.6 Patients must have normal organ and marrow function as defined below:

          -  absolute neutrophil count greater than or equal to1,500/mcL

          -  platelets greater than or equal to 50,000/mcL

          -  total bilirubin less than or equal to 1.5 X institutional upper limit of normal

          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
             (SGOT)/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT) less
             than or equal to 3 X institutional upper limit of normal

          -  estimated glomerular filtration rate (GFR) (calculated using Chronic Kidney Disease
             Epidemiology Collaboration (CKD-EPI) equation) greater than or equal to 30 mL/min/1.73
             sq.m.

        3.1.1.7 Computerized Tomography (CT) urogram or Magnetic Resonance Imaging (MRI) urogram.
        If urogram protocol not available or contrast allergy/poor renal function preclude such
        imaging, then noncontrast CT or MRI of the abdomen/pelvis within 45 days of study entry
        will suffice.

        3.1.1.8 Chest x-ray negative for metastatic disease.

        3.1.1.9 Ability of patient to understand and the willingness to sign a written informed
        consent document.

        EXCLUSION CRITERIA:

        3.1.2.1 Previous pelvic radiation for bladder or prostate cancer if performed <12 months
        prior to enrollment into the study.

        3.1.2.2 Patients who are receiving any other concurrent investigational agents (patients
        are eligible to enroll 4 weeks after completion of prior agent).

        3.1.2.3 Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
        mitomycin C) prior to entering the study or those who have not recovered from adverse
        events due to agents administered more than 4 weeks earlier. There will be at least a 3
        week delay from the time of a previous bladder biopsy/transurethral resection of bladder
        tumor (TURBT) to allow for adequate bladder healing prior to enrollment.

        3.1.2.4 Patients with a history of encephalitis, multiple sclerosis, or seizures within the
        last year (from seizure disorder or brain metastasis) should be excluded from this clinical
        trial because of their poor prognosis and because they often develop progressive neurologic
        dysfunction that would confound the evaluation of neurologic and other adverse events.

        3.1.2.5 History of allergy or untoward reaction to prior vaccination with vaccinia virus

        3.1.2.6 Patients should have no evidence of being immunocompromised as listed below:

          -  Human immunodeficiency virus positivity due to the potential for decreased tolerance
             and risk for severe side effects

          -  Active autoimmune diseases requiring treatment or a history of autoimmune disease that
             might be stimulated by vaccine treatment. This requirement is due to the potential
             risks of exacerbating autoimmunity. Patients with endocrine disease that is controlled
             by replacement therapy including thyroid disease and adrenal disease and vitiligo may
             be enrolled.

          -  History of splenectomy

        3.1.2.7 Uncontrolled intercurrent illness which would interfere with the ability of the
        patient to carry out the treatment program, including, but not limited to, active second
        malignancy other than a cancer that has been successfully treated resulting in a high
        likelihood of long-term survival (e.g. completely resected basal cell or squamous cell
        carcinoma of the skin, stage 1 renal cell carcinoma treated with partial nephrectomy,
        treated low risk prostate cancer, etc.), inflammatory bowel disease (e.g. Crohn's disease
        or ulcerative colitis), active diverticulitis, ongoing or active infection, symptomatic
        congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
        illness/social situations that would limit compliance with study requirements.

        3.1.2.8 Pregnant women are excluded from this study because the vaccines used in the study
        may have the potential for teratogenic or abortifacient effects. Because there is an
        unknown but potential risk for adverse events in nursing infants secondary to treatment of
        the mother with the vaccine, breastfeeding should be discontinued if the mother is treated
        with vaccines. These potential risks may also apply to other agents used in this study.
        Patients must agree to use adequate contraception (hormonal or barrier method of birth
        control; abstinence) prior to study entry and for the duration of study participation.
        Should a woman become pregnant or suspect she is pregnant while her partner is
        participating in this study, she should inform her treating physician immediately

        3.1.2.9 Concurrent use of systemic steroids, except for physiologic doses of systemic
        steroids for replacement or local (topical, nasal, or inhaled) steroid use. Limited doses
        of systemic steroids to prevent intravenous (IV) contrast, allergic reaction, or
        anaphylaxis (in patients who have known contrast allergies) are allowed. Although topical
        steroids are allowed, steroid eye-drops are contraindicated

        3.1.2.10 Altered immune function, including immunodeficiency or history of
        immunodeficiency; eczema; history of eczema, or other eczematoid skin disorders; or those
        with acute, chronic or exfoliative skin conditions (e.g. atopic dermatitis, burns,
        impetigo, varicella zoster, severe acne, or other open rashes or wounds). There is an
        increased risk to patients or contacts with eczema, atopic dermatis, and other immune
        deficiencies who are at risk for eczema vaccination.

        3.1.2.11 Medical conditions which, in the opinion of the investigators, would jeopardize
        the patient or the integrity of the data obtained

        3.1.2.12 Serious hypersensitivity reaction to egg products

        3.1.2.13 Chronic hepatitis infection, including B and C, because of potential immune
        impairment

        3.1.2.14 Clinically significant cardiomyopathy or cardiac complications, including recent
        myocardial infarction or cerebrovascular accident within one year, and/or unstable or
        uncontrolled angina

        3.1.2.15 Previous intolerance to BCG intravesical therapy suggested by development of
        systemic BCG infection in the past and/or grade 4 or greater adverse effect by Common
        Terminology Criteria in Adverse Events (CTCAE) v4.0.

        3.1.2.16 Patients unable to avoid close contact or household contact with the following
        high-risk individuals for three weeks after the Day 1 vaccination: (a) children less than
        or equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or
        concurrent extensive eczema or other eczematoid skin disorders, or (d) immunocompromised
        individuals, such as those with human immunodeficiency virus (HIV).

        3.1.3 Inclusion of Women and Minorities:

        Both men and women of all races and ethnic groups are eligible for this trial.