Intravesical Administration of rAd-IFN/Syn3 in Patients With BCG-Refractory or Relapsed Bladder Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2, Randomized, Open Label, Parallel Arm Study to Evaluate the Safety and Efficacy of rAd-IFN/Syn3 Following Intravesical Administration in Subjects With High Grade, BCG Refractory or Relapsed Superficial Bladder Cancer

Conditions
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Superficial Bladder Cancer

Intervention / Treatment
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* Drug: INSTILADRIN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older at the time of consent Able to give informed consent 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 Complete resection of visible papillary lesions or CIS by TURBT or endoscopic resection between 14 and 60 days prior to beginning study treatment Available for the whole duration of the study Life expectancy >2 years, in the opinion of the investigator ECOG status 2 or less Absence of upper tract urothelial carcinoma 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. 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. 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: Current or previous evidence of muscle invasive or metastatic disease Current systemic therapy for bladder cancer Current or prior pelvic external beam radiotherapy Prior treatment with adenovirus-based drugs Suspected hypersensitivity to interferon alpha Existing urinary tract infection or bacterial cystitis Clinically significant and unexplained elevated liver or renal function tests Women who are pregnant or lactating Severe cardiovascular disease History of malignancy of other organ system within past 5 years (except treated basal cell carcinoma or squamous cell carcinoma of the skin) Subjects who cannot hold instillation for 1 hour Subjects who cannot tolerate intravesical dosing or intravesical surgical manipulation Intravesical therapy within 6 weeks of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rAd-IFN Dose 1x10^11vps/ml<br>Subjects will be randomly assigned to one of two INSTILADRIN arms. | Drug: INSTILADRIN<br>* The INSTILADRIN components will be mixed with a diluent. The total dose will be given as a single, one-hour intravesical administration which may, depending on clinical response, be repeated every 3 months up to a maximum of 4 instillations.<br>* Other names: rAd-IFN/Syn3;|
| Experimental: rAd-IFN dose 3x10^11 vps/ml<br>Subjects will be randomly assigned to one of two INSTILADRIN arms. | Drug: INSTILADRIN<br>* The INSTILADRIN components will be mixed with a diluent. The total dose will be given as a single, one-hour intravesical administration which may, depending on clinical response, be repeated every 3 months up to a maximum of 4 instillations.<br>* Other names: rAd-IFN/Syn3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of High Grade-Recurrence Free Survival at 360 Days | Following the initial treatment, patients were clinically evaluated and re-treated at the Days 90, 180, and 270 time points, as outlined below. The decision to repeat treatment was determined by the clinical response observed following the previous treatment(s). Patients were assessed for High-Grade disease recurrence by cytology, cystoscopy and, if clinically indicated, biopsies were performed to obtain accurate staging. If no evidence of recurrence of High-Grade disease was detected, then a further dose of rAd-IFN/Syn3 was administered as maintenance therapy. Patients who had recurrence of High-Grade disease were withdrawn from treatment but were followed for survival and time to cystectomy. At 360 Days, a final efficacy evaluation was performed for patients receiving 4 doses of drug. This included cystoscopy, cytology, and biopsy. | 360 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of rAd-IFN/Syn3 | Treatment Emergent Adverse Events (AEs) for patients receiving study drug were described by NCI-CTCAE V4.03 terminology according to System Organ Class. | 360 Days | 
| Incidence of High Grade Recurrence-Free Survival at 3 Months (90 Days). | All patients were evaluated 3 Months (90 Days) after the start of treatment for recurrence of high grade disease by cytology, cystoscopy, and biopsy if clinically indicated. Patients that we free of High-Grade disease recurrence received another dose. Data are presented as the number and percent of patients with High-Grade disease recurrence. | 90 Days | 
| Incidence of High Grade-Recurrence-Free Survival at 6 Months (180 Days). | All patients were evaluated 6 Months (180 Days) after the start of treatment for recurrence of high grade disease by cytology, cystoscopy, and biopsy if clinically indicated. Patients that we free of High-Grade disease recurrence received another dose. Data are presented as the number and percent of patients with High-Grade disease recurrence. | 180 Days | 
| Incidence of High Grade-Recurrence-Free Survival at 9 Months (270 Days). | All patients were evaluated 9 Months (270 Days) after the start of treatment for recurrence of high grade disease by cytology, cystoscopy, and biopsy if clinically indicated. Patients that we free of High-Grade disease recurrence received a final dose. Data are presented as the number and percent of patients with High-Grade disease recurrence. | 270 Days | 
| Incidence of Cystectomy in All Patients | This secondary objective measures the incidence of cystectomy at 360 Days for the Efficacy Analysis Set. | 360 Days | 
| Overall Survival in All Patients. | Overall survival was defined as the number who survived from the first dose of rAd-IFN/Syn3 to the end of the primary assessment (360 Days) or Withdrawal. | 360 Days | 
| Number of Patients With Elevated Levels of Viral Vector in Blood | The level of viral vector as measured by qPCR in blood was determined in all patients on the initial day of dosing Day 1 (pre-dose) and at Day 2, Day 4, Day 12, and for patients that were free of High-Grade disease recurrence and received a second dose at Day 91 (pre-dose), Day 92, Day 94, and Day 103. | 103 Days | 
| Number of Patients With Elevated Levels of Viral Vector in Urine | The level of viral vector as measured by qPCR in urine was determined in all patients on the initial day of dosing Day 1 (pre-dose) and at Day 2, Day 4, Day 12, and for patients that were free of High-Grade disease recurrence and received a second dose at Day 91 (pre-dose), Day 92, Day 94, and Day 103. | 103 Days | 
| Number of Patients With Elevated IFN alpha2b Protein Levels in Serum | The levels of serum IFN alpha2b protein as measured by ELISA were determined in all patients on the initial day of dosing (Pre-Dose Day 1), at Day 2, Day 4, Day 12, and for patients that were free of High-Grade disease recurrence and received subsequent doses at Day 91 (pre-dose), Day 92, Day 94, Day 103, Day 180 (pre-dose), Day 270 (pre-dose), and Day 360 or Withdrawal. | 360 Days | 
| Number of Patients With Elevated IFN alpha2b Protein Levels in Urine | The levels of urine IFN alpha2b protein as measured by ELISA were measured in all patients on the initial day of dosing Day 1 (pre-dose) and at Day 2, Day 4, Day 12, and for patients that did not have recurrence of HGD and received a second dose at Day 91 (pre-dose), Day 92, Day 94, and Day 103. | 103 Days | 
| Number of Patients With Elevated Levels of Anti-IFN alpha2b Antibodies in Serum | The levels of serum anti-IFN alpha2b antibodies as measured by ELISA were determined in all patients on the initial day of dosing (Pre-Dose Day 1), at Day 12, and for patients that were free of High-Grade disease recurrence and received subsequent doses at Day 180 (pre-dose), Day 270 (pre-dose), and Day 360 or Withdrawal. | 360 Days | 
| Number of Patients With Elevated Levels of Anti-Adenovirus Type 5 Antibodies in Serum. | The levels of serum anti-adenovirus type 5 antibodies as measured by ELISA were determined in all patients on the initial day of dosing (Pre-Dose Day 1), at Day 12, and for patients that were free of High-Grade disease recurrence and received subsequent subsequent doses at Day 180 (pre-dose), Day 270 (pre-dose), and Day 360 or Withdrawal. | 360 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCG Refractory or Relapsed Superficial Bladder Cancer, rAd-IFN, Syn3, Intravesical, transitional cell carcinoma of the bladder, superficial non-muscle invasive tumor, Interferon alpha2b, INSTILADRIN