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 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
CD4 and 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, 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: 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 HLA-A2 agonist epitopes) as well as 3 human T-cell
costimulatory molecules, B7-1, ICAM-1, and LFA-3 [rV-PANVAC (vaccinia) and rFPANVAC
(fowlpox)] as follows:

- rV-PANVAC 2 x 10(8) pfu 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.

- 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 CIS
confirmed by the Laboratory of Pathology, 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 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 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

- AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of normal

- estimated GFR (calculated using 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/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 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 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 eczemoid skin disorders, or (d) immunocompromised
individuals, such as those with HIV.

3.1.3 Inclusion of Women and Minorities:

Both men and women of all races and ethnic groups are eligible for this trial.