Intravesical Administration of rAd-IFN/Syn3 in Patients With BCG-Refractory or Relapsed Bladder Cancer
Intravesical Administration of rAd-IFN/Syn3 in Patients With BCG-Refractory or Relapsed Bladder Cancer
This Phase 2 study is designed to assess the efficacy and safety of INSTILADRIN (rAd-IFN with
 Syn3) when given intravesically to patients with high grade non-muscle invasive bladder
 cancer who are refractory to or have relapsed from BCG therapy. The pharmacodynamics of
 INSTILADRIN will also be studied by measuring the interferon (IFNα2b) levels excreted in the
 urine. rAd-IFN is a non-replicating recombinant adenovirus type 5 (Ad5)-vector encoding the
 interferon alpha-2b (IFNα2b) gene. Syn 3 is clinical surfactant excipient which enhances the
 ability of the adenoviral vector to transfect cells in the bladder wall.
Criteria for Evaluation:

 Efficacy: A Response is defined as no evidence of recurrence of a high grade tumor by
 cystoscopy, cytology or if clinically indicated, biopsy.

 Safety: The safety and tolerability of INSTILADRIN will be evaluated based on adverse event
 reports, vital signs, ECGs, clinical laboratory values and results of physical examination.
Inclusion Criteria:

 1. Aged 18 years or older at the time of consent

 2. Able to give informed consent

 3. Subjects with high grade BCG-refractory or relapsed NMIBC including

 -  High grade non-invasive papillary carcinomas (Ta) and subjects with high grade
 tumors that invade sub-epithelial connective tissue (T1) or

 -  Carcinoma in situ (CIS) only or

 -  CIS and Ta or T1 tumors Refractory is defined as failure to achieve a
 disease-free state at six months after adequate induction of BCG therapy with
 either maintenance or re-induction at 3 months. Adequate induction is defined as
 a minimum of 5 out of 6 induction doses and adequate maintenance is defined as a
 minimum of 2 out of 3 doses of treatment.

 Relapse is defined as recurrence within 1 year after a complete response to BCG
 treatment

 4. Complete resection of visible papillary lesions or CIS by TURBT or endoscopic
 resection between 14 and 60 days prior to beginning study treatment

 5. Available for the whole duration of the study

 6. Life expectancy >2 years, in the opinion of the investigator

 7. ECOG status 2 or less

 8. Absence of upper tract urothelial carcinoma

 9. Female subjects of childbearing potential must use maximally effective birth control
 during the period of therapy, must be willing to use contraception for 1 month
 following the last study drug infusion and must have a negative urine or serum
 pregnancy test upon entry into this study. Otherwise, female subjects must be
 postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile.

 10. Male subjects must be surgically sterile or willing to use a double barrier
 contraception method upon enrollment, during the course of the study, and for 1 month
 following the last study drug infusion.

 11. Adequate laboratory values.

 -  Hemoglobin ≥10 g/dL.

 -  WBC ≥4000/μL.

 -  ANC ≥2000/μL.

 -  Platelet count ≥100,000/μL.

 -  INR within institutional normal limits.

 -  aPTT within institutional normal limits.

 -  AST ≤1.5 x ULN.

 -  ALT ≤1.5 x ULN.

 -  Total bilirubin within institutional normal limits.

 -  Creatinine ≤1.5 x ULN.

 Exclusion Criteria:

 1. Current or previous evidence of muscle invasive or metastatic disease

 2. Current systemic therapy for bladder cancer

 3. Current or prior pelvic external beam radiotherapy

 4. Prior treatment with adenovirus-based drugs

 5. Suspected hypersensitivity to interferon alpha

 6. Existing urinary tract infection or bacterial cystitis

 7. Clinically significant and unexplained elevated liver or renal function tests

 8. Women who are pregnant or lactating

 9. Severe cardiovascular disease

 10. History of malignancy of other organ system within past 5 years (except treated basal
 cell carcinoma or squamous cell carcinoma of the skin)

 11. Subjects who cannot hold instillation for 1 hour

 12. Subjects who cannot tolerate intravesical dosing or intravesical surgical manipulation

 13. Intravesical therapy within 6 weeks of enrollment