Bacillus Calmette-Guerin Followed by Sunitinib for the Treatment of High Risk Non-muscle Invasive Lower Urinary Tract Urothelial Carcinoma

Despite a complete response of 45-55% in patients with non-muscle invasive urothelial
carcinoma involving the lower urinary tract at 3 months, many patients suffer from multiple
recurrences and progression in up to 1/3 of patients. While radical cystectomy is an
effective local therapy for patients with high risk non-invasive disease, roughly 15% of
patients will still develop progression. More importantly, the morbidity of radical
cystectomy as described above represents a barrier to treatment in some individuals. Thus,
there is a real need to identify newer therapies that reduce morbidity and improve outcomes
in patients with non-invasive urothelial cancer. While multiple drug regimens have been the
standard for many forms of cancer including invasive bladder cancer, few reports exist on
multidrug regimens for non-invasive bladder cancer.

The fundamentally agreed upon mechanism of action of BCG intravesical therapy for superficial
bladder cancer is the generation of a non-specific immune response with the expression of
cytokines by inflammatory cells resulting in tumor death. Cytokines produced by BCG therapy
such as IFNα may block vascular endothelial growth factor (VEGF) which is expressed in
superficial and invasive bladder cancer and may provide a mechanism for disease progression.

Sunitinib is an oral tyrosine kinase inhibitor that blocks VEGF. Recent reports demonstrate
clinical response in patients with metastatic bladder cancer treated with sunitinib after
recurrence following standard chemotherapeutic regimens. The addition of sunitinib following
BCG in order to consolidate VEGF inhibition may result in superior 3 month complete response
rates. We know that patients who have a complete response to BCG at 3 months have improved
disease.

Inclusion Criteria:

- Patients must have histologically confirmed urothelial carcinoma confined to the
urinary bladder and/or prostatic urethra by bladder biopsy within 6 weeks of study
enrollment.

- Patients are eligible if the biopsy was done within 3 months of enrollment and a
cystoscopy demonstrates no gross disease within 6 weeks of enrollment.

- Tumor histology with >50% transitional cell carcinoma histology

- Tumor stage less than or equal to T1 confirmed by pathology report

- Patients with a T1 tumor will require a restaging TURBT confirming no higher stage
tumor prior to study enrollment

- High grade tumor as defined by the WHO/ISUP 1998 classification system. (Presence of
carcinoma in situ constitutes a high grade tumor)

- No BCG within 12 months of enrollment

- Patients are allowed to have received a single dose of intravesical chemotherapy
(excluding BCG) in the operating room following transurethral resection documenting
non-muscle invasive urothelial carcinoma of the lower urinary tract.

- Patients are allowed to have received a previous 6 week cycle of any standard
intravesical chemotherapy if > 3 months prior to enrollment.

- Age >18 years.

- ECOG performance status 0 or 1

- Patients must have adequate organ and marrow function as defined below:

- absolute neutrophil count > 1,500/mcL

- platelets > 100,000/mcL

- total bilirubin less than or equal to 1.5 upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper

- limit of normal

- Serum creatinine < 2.0 mg/dl

- MUGA scan within institutional normal limits

- Timing guideline for pre-study labs and measurements:

- All pre-study labs required for determination of eligibility are to be completed
within 6 weeks prior to registration.

- X-rays and/or scans to determine disease status are to be completed within 6 months
prior to registration (or the next business day if falls on a weekend or holiday).

Exclusion Criteria:

- Patients with a prior history of radiation for bladder cancer

- Patients with a prior history of radiation for prostate cancer are eligible for the
study

- Greater than or equal to T2N0M0 transitional cell carcinoma of the bladder on current
pathology or in the past

- Patients with a prior history of upper tract urothelial carcinoma are eligible for
participation in the study as long as there is no evidence of disease for 6 months
prior to study enrollment

- Patients with other malignancies are eligible for enrollment in the study but should
not be on active treatment for this malignancy within 12 months of study enrollment.
Patients with prior history of local treatment for prostate cancer are eligible for
participation in the study

- Patients cannot have received Sunitinib or other anti-angiogenic therapy for at least
12 months prior to enrollment in the study

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BCG and Sunitinib

- Patients with prior systemic infection with BCG are not eligible for the study

- Patients with prior intolerance to BCG may be considered

- Major incisional surgery within 4 weeks of study enrollment

- Bleeding diathesis or unresolved gross hematuria after bladder biopsy

- Known HIV - positive patients may not participate. This is to avoid additional
complications that immune suppression and HIV infection may cause due to treatment
with BCG, which is a live attenuated bacteria that is known to cause systemic
infection in patients who are immunocompromised.

- Patients taking agents that result in immunosuppression are not eligible for the study
due to the potential for the increased risk of systemic infection in those patients
receiving BCG

- Any of the following within the 6 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure (CHF), cerebrovascular accident or
transient ischemic attack, or pulmonary embolism.

- Ongoing cardiac dysrhythmias of NCI CTCAE grade 2.

- Patients with history of or who are suspected to have CHF can be included as long as
they are asymptomatic and have an ejection fraction that is equal to or above the
institutional lower limit of normal by baseline MUGA (obtained within 28 days of
registration or the next business day if falls on a weekend or holiday).

- QTc interval > 500 msec on baseline EKG (to be done within 6 weeks prior to
registration or the next business day if falls on a weekend or holiday).

- Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal
medical therapy).

- Patient may not have unresolved bacterial infection.

- Patients with hypothyroidism that can not be adequately controlled with medication
will be excluded. All patients will be monitored at trial initiation with a TSH.

- Concurrent treatment on another clinical trial. Supportive care trials or
non-treatment trials, e.g. QOL, are allowed.

- Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy.

- All female subjects with reproductive potential must have a negative pregnancy test
(serum or urine) prior to enrollment.

- Male subjects must be surgically sterile or must agree to use effective contraception
during the period of therapy.

- The definition of effective contraception will be based on the judgment of the
principal investigator or a designated associate.

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the subject inappropriate for entry into
this study.