ADSTILADRIN (=INSTILADRIN) in Patients With High-Grade, Bacillus Calmette-Guerin (BCG) Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)

Phase 3

Completed

• Conditions: Superficial Bladder Cancer
• Interventions: Biological: ADSTILADRIN

• Registration Number: NCT02773849
• Lead Sponsor: Ferring Pharmaceuticals

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2016-04-19
• Study First Submitted QC: 2016-05-12
• Study First Posted: 2016-05-16
• Study Start: 2016-09-19
• Primary Completion: 2019-05-24
• Disposition First Submitted: 2020-05-11
• Disposition First Submitted QC: 2020-05-11
• Disposition First Posted: 2020-05-13
• Results First Submitted: 2022-05-11
• Results First Submitted QC: 2022-06-17
• Results First Posted: 2022-07-13
• Study Completion: 2023-05-24
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-26
• Last Update Posted: 2024-07-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 157

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ADSTILADRIN	ADSTILADRIN	Intravesical administration of ADSTILADRIN into the bladder

Primary Outcome Measures

Name	Time	Method
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.	12 Months	A patient in the CIS cohort was judged to have achieved CR where urine cytology was reported as normal, atypical, degenerative, reactive, inflammatory, or nonspecific AND cystoscopy was reported as normal or with findings that did not include evidence of low-grade or high-grade recurrence. Bladder biopsy, if performed (not mandatory), demonstrated an absence of low-grade or high-grade recurrence.

Secondary Outcome Measures

Name	Time	Method
Durability of High-grade-recurrence-free Survival in Patients With High-grade Ta or T1 Papillary Disease (With or Without Concomitant CIS)	Up to 57 months	HGRF survival was defined as the time from the first dose to the first recurrence of high-grade disease (including muscle-invasive disease progression and death due to any cause). Patients without high-grade disease recurrence were censored at the last disease assessment not showing high-grade disease recurrence.
Safety of ADSTILADRIN	60 Months	The type, incidence, relatedness and severity of treatment emergent adverse events of ADSTILADRIN as assessed by NCI-CTCAE V4.03 were monitored.
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)	up to 57 months	Complete response rate will be measured by determining the number of patients without recurrence of high-grade disease using results from urine cytology, cystoscopy, and biopsy of the bladder. Incidence of HGRF survival at Months 3, 6, 9, and 12, and every 3 months up to Month 24, and then at Months 36, 48, and 57.
Incidence of Cystectomy at 12 Months, 2 Years and 5 Years	60 Months	The incidence of cystectomy is described as the proportion of patients undergoing radical cystectomy for any reason after the first dose, within 12 months, 2 years and 5 years.
Anti-adenoviral Antibody Levels for Correlation to Response Rate	12 Months	Measurement of anti-adenoviral antibody levels at each dosing period, withdrawal, and at 12 months were done. A patient was considered to have a positive immunogenic response in anti-adenoviral antibodies if a post-baseline titration demonstrated a greater than a 2-fold dilution increase from baseline.; The table represent data at any time during the 12 months period, which means that the patients were included in the Yes group if they at any measurement during the trial had a 2-fold dilution increase from baseline.
Durability of Complete Response in Patients With CIS (With or Without Concomitant Ta or T1 Papillary Disease) Who Achieve a Complete Response.	Up to 57 months	Durability of complete response (CR) was defined as the time from first observed CR to the documented treatment failure. Patients without treatment failure were censored at the last disease assessment not showing treatment failure, where treatment failure was defined as high-grade disease recurrence, disease progression, or death, whichever occurred earlier.
Overall Survival Rate in All Patients	60 Months	Overall survival rate was defined as the time from the first dose to death due to any cause. Patients who were still alive were censored at the last date the patient was known to be alive. Overall survival rate is a Kaplan-Meier estimate of the survivor function at each specific time point. The 95% CI is calculated using the Greenwood's formula with a log-log transformation. Percentage is calculated using the number of patients in the column heading as the denominator.
Durability of Response During the Long-term Follow-up Period.	Up to 60 Months	Durability will be measured by determining the number of patients without recurrence of high-grade disease using results from urine cytology, cystoscopy, and biopsy of the bladder if clinically indicated.

Trial Locations

Locations (34)

University of Virginia Health System; 🇺🇸 Charlottesville, Virginia, United States

Spectrum Health Medical Group; 🇺🇸 Grand Rapids, Michigan, United States

West Virginia University Cancer Institute; 🇺🇸 Morgantown, West Virginia, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Penn State Milton S. Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

SUNY Upstate Medical Center; 🇺🇸 Syracuse, New York, United States

Delaware Valley Urology, LLC; 🇺🇸 Voorhees, New Jersey, United States

Regional Urology; 🇺🇸 Greenville, South Carolina, United States

Carolina Urologic research Center; 🇺🇸 Myrtle Beach, South Carolina, United States

Banner MD Anderson Cancer Center; 🇺🇸 Gilbert, Arizona, United States

The Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Duke University; 🇺🇸 Durham, North Carolina, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Johns Hopkins Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Emory University School of Medicine; 🇺🇸 Atlanta, Georgia, United States

University of Chicago - Comprehensive Cancer Research Center; 🇺🇸 Chicago, Illinois, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States

The University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Vanderbilt University Medical Center Dept. of Urologic Surgery; 🇺🇸 Nashville, Tennessee, United States

The Urology Center of Colorado; 🇺🇸 Denver, Colorado, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Keck School of Medicine at USC Medical Center; 🇺🇸 Los Angeles, California, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

The Univ. of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, Texas, United States

Urology of Virginia; 🇺🇸 Virginia Beach, Virginia, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

H. Lee Moffitt Cancer Center & Research Institute; 🇺🇸 Tampa, Florida, United States

Ochsner Clinic Foundation; 🇺🇸 New Orleans, Louisiana, United States

University of North Carolina (UNC) - Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

University of Florida - UF Health Davis Center Pavilion and Shands Med Plaza; 🇺🇸 Gainesville, Florida, United States

University of Wisconsin - Madison; 🇺🇸 Madison, Wisconsin, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States