Clinical trial NCT01687244: Intravesical Administration of rAd-IFN/Syn3 in Patients With BCG-Refractory or Relapsed Bladder Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Superficial Bladder Cancer
Keywords: 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
Lead sponsor: FKD Therapies Oy
Sponsor class: INDUSTRY
First posted: 2012-09-18
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of High Grade-Recurrence Free Survival at 360 Days
timeFrame: 360 Days
Secondary outcomes:
measure: Safety of rAd-IFN/Syn3
timeFrame: 360 Days
measure: Incidence of High Grade Recurrence-Free Survival at 3 Months (90 Days).
timeFrame: 90 Days
measure: Incidence of High Grade-Recurrence-Free Survival at 6 Months (180 Days).
timeFrame: 180 Days
measure: Incidence of High Grade-Recurrence-Free Survival at 9 Months (270 Days).
timeFrame: 270 Days
measure: Incidence of Cystectomy in All Patients
timeFrame: 360 Days
measure: Overall Survival in All Patients.
timeFrame: 360 Days
measure: Number of Patients With Elevated Levels of Viral Vector in Blood
timeFrame: 103 Days
measure: Number of Patients With Elevated Levels of Viral Vector in Urine
timeFrame: 103 Days
measure: Number of Patients With Elevated IFN alpha2b Protein Levels in Serum
timeFrame: 360 Days
measure: Number of Patients With Elevated IFN alpha2b Protein Levels in Urine
timeFrame: 103 Days
measure: Number of Patients With Elevated Levels of Anti-IFN alpha2b Antibodies in Serum
timeFrame: 360 Days
measure: Number of Patients With Elevated Levels of Anti-Adenovirus Type 5 Antibodies in Serum.
timeFrame: 360 Days
Other outcomes:
Locations:
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Colin Dinney, MD
role: STUDY_CHAIR
References:
citation: Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, Gomella LG, Kamat AM, Lotan Y, Svatek RS, Bivalacqua TJ, Grubb RL 3rd, Krupski TL, Lerner SP, Woods ME, Inman BA, Milowsky MI, Boyd A, Treasure FP, Gregory G, Sawutz DG, Yla-Herttuala S, Parker NR, Dinney CPN. Intravesical rAd-IFNalpha/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol. 2017 Oct 20;35(30):3410-3416. doi: 10.1200/JCO.2017.72.3064. Epub 2017 Aug 23.