Clinical trial NCT02773849: ADSTILADRIN (=INSTILADRIN) in Patients With High-Grade, Bacillus Calmette-Guerin (BCG) Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)
Official title: A Phase III, Open Label Study to Evaluate the Safety and Efficacy of INSTILADRIN® (rAd-IFN)/Syn3) Administered Intravesically to Patients With High-Grade, BCG Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Superficial Bladder Cancer
Keywords: IFN
BCG-unresponsive
Non-Muscle Invasive Bladder Cancer (NMIBC)
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: FKD Therapies Oy
name: Society of Urologic Oncology Clinical Trials Consortium
First posted: 2016-05-16
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Previous multi-dose Phase I and Phase II clinical studies have demonstrated that ADSTILADRIN is a safe and effective treatment for BCG-refractory and recurrent NMIBC. This Phase III study is designed to expand those observations using a high dose of ADSTILADRIN in patients that are "BCG Unresponsive" which refers to patients with high-grade NMIBC who are unlikely to benefit from and should not receive further intravesical BCG.

Detailed description: Recombinant IFN alpha2b has pleiotropic effects that contribute to antitumor activity in Non-Muscle Invasive Bladder Cancer (NMIBC). ADSTILADRIN is a non-replicating adenovirus vector harboring the human IFN alpha2b gene. When combined with the excipient Syn3, intravesical administration of the rAd-IFN results in transduction of the virus into the epithelial cell lining in the bladder. The IFN alpha2b gene is incorporated into the cellular DNA resulting in the synthesis and expression of large amounts of IFN alpha2b protein. Clinical studies have confirmed that IFN alpha2b protein can be measured in the urine of patients treated with ADSTILADRIN within 24 hours after dosing.

Eligibility criteria: Inclusion Criteria:

1. Aged 18 years or older at the time of consent
2. Able to give informed consent
3. Had, at entry, confirmed by a pathology report:

   Carcinoma in situ (CIS) only; Ta/T1 high-grade disease with concomitant CIS; or Ta/T1 high-grade disease without concomitant CIS
4. Are "BCG Unresponsive" which refers to patients with high-grade NMIBC who were unlikely to benefit from and who did not receive further intravesical BCG. The term "BCG unresponsive" included patients who did not respond to BCG treatment and had a persistent high-grade recurrence within 12 months after BCG was initiated, and those who despite an initial complete response (CR) to BCG, relapsed with high-grade CIS within 12 months of their last intravesical treatment with BCG or relapsed with high-grade Ta/T1 NMIBC within 6 months of their last intravesical treatment with BCG. The following criteria defined the patients who were eligible for inclusion in the study:

   * Had received at least 2 previous courses of BCG within a 12 month period. This was defined as at least 5 of 6 induction BCG instillations and at least 2 out of 3 instillations of maintenance BCG, or at least 2 of 6 instillations of a second induction course, where maintenance BCG was not given;

     * Exception: those who had T1 high-grade disease at first evaluation after induction BCG alone (at least 5 of 6 doses) qualified in the absence of disease progression.
   * At the time of tumor recurrence, patients with CIS alone or high-grade Ta/T1 with CIS were within 12 months of last exposure to BCG and patients with high-grade Ta/T1 without CIS were within 6 months of last exposure to BCG;
   * No maximum limit to the amount of BCG administered; and
   * All visible papillary tumors were required to be resected and those with persistent T1 disease on transurethral resection of bladder tumor (TURBT) underwent an additional re-TURBT within 14 to 60 days prior to beginning study treatment. Obvious areas of CIS should also be fulgurated.
5. Available for the whole duration of the study
6. Life expectancy \>2 years, in the opinion of the investigator
7. Eastern Cooperative Oncology Group (ECOG) status 2 or less
8. Absence of concomitant upper tract urothelial carcinoma or urothelial carcinoma within the prostatic urethra. Freedom from upper tract disease (if clinically indicated) as indicated by no evidence of upper tract tumor by either intravenous pyelogram, retrograde pyelogram, computed tomography (CT) scan with or without urogram, or magnetic resonance imaging (MRI) with or without urogram performed within 6 months of enrollment
9. Patients with prostate cancer on active surveillance at low risk for progression, defined as Prostate-Specific Antigen (PSA) \< 10 ng/dL, Gleason score 6 and clinical stage tumor-1 (cT1) were permitted to be in the study at the discretion of the investigator (see exclusion criterion 10).
10. Female patients of childbearing potential were required to use maximally effective birth control during the period of therapy, were required to use contraception for 1 month following the last study drug infusion and were required to have a negative urine or serum pregnancy test upon entry into this study. Otherwise, female patients were required to be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile. 'Maximally effective birth control' meant that the patient, if sexually active, used a combination of two methods of birth control that were approved and recognized to be effective by Regulatory Agencies
11. Male patients were required to 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; and
12. Adequate lab values

Exclusion Criteria:

1. Current or previous evidence of muscle invasive (muscularis propria) or metastatic disease presented at the screening visit. Examples of increased risk of metastatic disease included (but were not limited to):

   * Presence of lymphovascular invasion and/micropapillary disease as shown in the histology of the biopsy sample; and
   * Patients with T1 disease accompanied by the presence of hydronephrosis secondary to the primary tumor
2. Current systemic therapy for bladder cancer
3. Current or prior pelvic external beam radiotherapy within 5 years of entry
4. Prior treatment with adenovirus-based drugs
5. Suspected hypersensitivity to IFN alfa2b
6. Symptomatic urinary tract infection or bacterial cystitis (once satisfactorily treated, patients could have entered the study)
7. Clinically significant and unexplained elevated liver or renal function tests
8. Women who were pregnant or lactating or refused to commit to use contraception throughout the study
9. Any other significant disease or other clinical findings which, in the opinion of the investigator, prevented study entry
10. History of malignancy of another organ system within the past 5 years, except treated basal cell carcinoma or squamous cell carcinoma of the skin and ≤ pathological tumor-2 (pT2) upper tract urothelial carcinoma at least 24 months after nephroureterectomy. Also patients with genitourinary cancers other than urothelial cancer or prostate cancer that were under active surveillance were excluded (see inclusion criterion 9)
11. Patients who could not hold instillation for 1 hour
12. Patients who could not tolerate intravesical dosing or intravesical surgical manipulation; and
13. Intravesical therapy within 8 weeks prior to beginning study treatment with the exception of:

    * cytotoxic agents (e.g. Mitomycin C, doxorubicin and epirubicin) when administered as a single instillation immediately following a TURBT procedure which was permitted between 14 to 60 days prior to beginning study treatment
    * previous intravesical BCG therapy, which could be given at least 5 weeks before the diagnostic biopsy required for entry into the study

Primary outcomes:
measure: Number of Patients With a Complete Response Rate Based on Patients With Carcinoma in Situ (CIS), With or Without Concomitant High-grade Ta or T1 Papillary Disease.
timeFrame: 12 Months
Secondary outcomes:
measure: Durability of Complete Response in Patients With CIS (With or Without Concomitant Ta or T1 Papillary Disease) Who Achieve a Complete Response.
timeFrame: Up to 57 months
measure: Rate of Event-free Survival, Where Event-free Survival is Defined as High-grade Recurrence Free (HGRF) Survival in Patients With High-grade Ta or T1 Disease (Without Concomitant CIS)
timeFrame: up to 57 months
measure: Durability of High-grade-recurrence-free Survival in Patients With High-grade Ta or T1 Papillary Disease (With or Without Concomitant CIS)
timeFrame: Up to 57 months
measure: Incidence of Cystectomy at 12 Months, 2 Years and 5 Years
timeFrame: 60 Months
measure: Overall Survival Rate in All Patients
timeFrame: 60 Months
measure: Anti-adenoviral Antibody Levels for Correlation to Response Rate
timeFrame: 12 Months
measure: Safety of ADSTILADRIN
timeFrame: 60 Months
measure: Durability of Response During the Long-term Follow-up Period.
timeFrame: Up to 60 Months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Keck School of Medicine at USC Medical Center
state: California
city: Denver
country: United States
facility: The Urology Center of Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida - UF Health Davis Center Pavilion and Shands Med Plaza
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: University of Chicago - Comprehensive Cancer Research Center
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Kimmel Cancer Center
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Medical Group
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Voorhees
country: United States
facility: Delaware Valley Urology, LLC
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina (UNC) - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Oklahoma City
country: United States
facility: The University of Oklahoma Health Sciences Center
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Greenville
country: United States
facility: Regional Urology
state: South Carolina
city: Myrtle Beach
country: United States
facility: Carolina Urologic research Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Dept. of Urologic Surgery
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: The Univ. of Texas Health Science Center at San Antonio
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Virginia Beach
country: United States
facility: Urology of Virginia
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University Cancer Institute
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
Study officials:
affiliation: Mayo Clinic
name: Stephen Boorjian, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, Bivalacqua TJ, Montgomery JS, Lerner SP, Busby JE, Poch M, Crispen PL, Steinberg GD, Schuckman AK, Downs TM, Svatek RS, Mashni J Jr, Lane BR, Guzzo TJ, Bratslavsky G, Karsh LI, Woods ME, Brown G, Canter D, Luchey A, Lotan Y, Krupski T, Inman BA, Williams MB, Cookson MS, Keegan KA, Andriole GL Jr, Sankin AI, Boyd A, O'Donnell MA, Sawutz D, Philipson R, Coll R, Narayan VM, Treasure FP, Yla-Herttuala S, Parker NR, Dinney CPN. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021 Jan;22(1):107-117. doi: 10.1016/S1470-2045(20)30540-4. Epub 2020 Nov 27.