Bacillus Calmette-Guerin Followed by Sunitinib for the Treatment of High Risk Non-muscle Invasive Lower Urinary Tract Urothelial Carcinoma
Condition: Urinary Tract Urothelial Carcinoma
MeSH terms: Carcinoma; Carcinoma, Transitional Cell
Intervention: Sunitinib
Intervention description: Patients are treated with a 6-week induction course of intravesical bacillus Calmette-Guerin (BCG) followed by a 2 week rest period and 4 week course of oral Sunitinib.
Patients will receive intravesical BCG (81 mg Theracys BCG in 50 ml normal saline) once weekly for 6 weeks within 6 weeks of bladder biopsy confirming high risk non-muscle invasive urothelial carcinoma. Two weeks after completion of BCG, patients will receive Sunitinib (50 mg daily) continuously for 28 days followed by a two week rest period. Patients will be reassessed with transurethral resection and urine cytology. Those with residual/recurrent disease will receive a second course identical to the initial protocol. Those with a complete response following initial or second treatment will be placed on maintenance BCG (3 week course every 6 months for 2 years). Those failing (progression, intolerance) initial/secondary treatments will be offered alternative therapy.
Intervention MeSH terms: Sunitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Bladder Cancer; High Risk Non-muscle Invasive Lower Urinary Tract Urothelial Carcinoma

Summary:

      A majority of patients with bladder cancer have disease confined to the inner lining of the
      bladder. Patients with high risk features (high grade tumors, tumors invading into a deeper
      superficial layer) are routinely treated with Bacillus Calmette Guerin (BCG) instilled in
      their bladder after the tumor has been removed. While up to 55% of patients respond to BCG,
      failure to respond may suggest a more aggressive tumor that requires more definitive therapy
      with complete bladder removal. BCG is believed to work by stimulating the body's own immune
      system to attack tumor cells. It may also work by blocking the machinery that tumors use to
      grow blood vessels which fuel tumor growth. A newer oral drug, sunitinib has shown to help
      patients with metastatic bladder cancer by blocking new blood vessel growth (VEGF
      inhibition). The investigators are studying the use of BCG followed by sunitinib in patients
      with high risk non-muscle invasive bladder cancer to evaluate the complete response (no
      visible evidence of tumor in the bladder) at 3 months and 6 months. The investigators will
      also evaluate whether there is recurrent tumor at three years.
    

Eligibility criteria:

        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.