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

• ClinicalTrials.gov Identifier: NCT02773849
• Recruitment Status: Completed
• First Posted: May 16, 2016
• Results First Posted: July 13, 2022
• Last Update Posted: December 22, 2023
• Sponsor: Ferring Pharmaceuticals
• Collaborators: FKD Therapies Oy; Society of Urologic Oncology Clinical Trials Consortium
• Information provided by (Responsible Party): Ferring Pharmaceuticals

Tracking Information

• First Submitted Date: April 19, 2016
• First Posted Date: May 16, 2016
• Results First Submitted Date: May 11, 2022
• Results First Posted Date: July 13, 2022
• Last Update Posted Date: December 22, 2023
• Actual Study Start Date: September 19, 2016
• Actual Primary Completion Date: May 24, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 17, 2022)

Number of Patients With a Complete Response Rate in Patients With Carcinoma in Situ (CIS), With or Without Concomitant High-grade Ta or T1 Papillary Disease. [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: May 12, 2016): Incidence of Event-Free Survival at 12 months, where Event-Free Survival is defined as High-Grade-Recurrence Free Survival [ Time Frame: 12 Months ]

Current Secondary Outcome Measures (submitted: June 17, 2022)

• Durability of Complete Response in Patients With CIS (With or Without Concomitant Ta or T1 Papillary Disease) Who Achieve a Complete Response. [ Time Frame: 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.
• Rate of Event-free Survival, Where Event-free Survival is Defined as High-grade Recurrence Free Survival in Patients With High-grade Ta or T1 Disease (Without Concomitant CIS) [ Time Frame: up to 60 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.
• Durability of Event-free Survival in Patients With High-grade Ta or T1 Papillary Disease (Without Concomitant CIS), Who Have no Recurrence of High-grade Ta or T1 Papillary Disease. [ Time Frame: 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.
• Incidence of Cystectomy in the Study [ Time Frame: 60 Months ]
  The incidence of and time to cystectomy will be measured in the study
• Overall Survival in All Patients [ Time Frame: 60 Months ]
  The incidence of and time to survival will be measured in the study
• Anti-adenoviral Antibody Levels for Correlation to Response Rate [ Time Frame: 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 2-fold increase from baseline. The table represent data at any time during the 12 months period, which means that the patient will be included in the Yes group if they at any measurement during the trial has a 2-fold increase from baseline.
• Safety of ADSTILADRIN [ Time Frame: 60 Months ]
  The type, incidence, relatedness and severity of treatment emergent adverse events of ADSTILADRIN as assessed by NCI-CTCAE V4.03 will be monitored.
• Durability of Response During the Long Term Follow up Period. [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: May 12, 2016)

• The incidence of Event-Free Survival where Event-Free Survival is defined as High-Grade-Recurrence Free Survival at 3, 6 and 9 months will be measured [ Time Frame: up to 9 months ]
  Incidence of Event-Free survival will be measured by determining the number of patients without recurrence of high grade disease using results from urine cytology, cystoscopic evaluation of the bladder, and biopsy pathology if clinically indicated.
• The type, incidence, relatedness and severity of treatment emergent adverse events of INSTILADRIN as assessed by NCI-CTCAE V4.03 will be monitored. [ Time Frame: 24 Months ]
• The number of patients requiring a cystectomy will be measured at 3, 6, 9, and 12 months. [ Time Frame: 3, 6, 9, and12 Months ]
• During the 12 month dosing period, the time to cystectomy for patients having the procedure will be measured. [ Time Frame: 12 Months ]
• The anti-adenoviral antibody levels in serum at each dosing period, withdrawal, and at 12 months will be measured. [ Time Frame: 12 Months ]
• The incidence of Event Free Survival during the Long Term Follow Up period after completing the Primary Outcome Measure will be measured. [ Time Frame: Up to 24 months ]
  Incidence of Event-Free survival will be measured by determining the number of patients without recurrence of high grade disease using results from urine cytology, cystoscopic evaluation of the bladder, and biopsy pathology if clinically indicated.
• Overall survival of patients enrolled in the study [ Time Frame: 12 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Superficial Bladder Cancer

Intervention

Biological: ADSTILADRIN

Other Names:

• rAd-IFN/SYN3NODA
• INSTILADRIN

Study Arms

Experimental: ADSTILADRIN

Intravesical administration of ADSTILADRIN into the bladder

Intervention: Biological: ADSTILADRIN

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 10, 2020): 157
• Original Estimated Enrollment (submitted: May 12, 2016): 135
• Actual Study Completion Date: May 24, 2023
• Actual Primary Completion Date: May 24, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Aged 18 years or older at the time of consent
2. Able to give informed consent

3. Have, 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 are unlikely to benefit from and who will not receiving further intravesical BCG. The term "BCG unresponsive" includes patients who did not respond to BCG treatment and have a persistent high-grade recurrence within 12 months after BCG was initiated, and those who despite an initial complete response (CR) to BCG, relapse with high-grade CIS within 12 months of their last intravesical treatment with BCG or relapse with high-grade Ta/T1 NMIBC within 6 months of their last intravesical treatment with BCG. The following criteria define the patients who may be included in the study:

   • Have received at least 2 previous courses of BCG within a 12 month period - defined as at least 5 of 6 induction BCG instillations and at least 2 out of 3 instillations of maintenance BCG, or at least two of six instillations of a second induction course, where maintenance BCG is not given

     • Exception: those who have T1 high-grade disease at first evaluation after induction BCG alone (at least 5 of 6 doses) may qualify in the absence of disease progression
   • At the time of tumor recurrence, patients with CIS alone or high-grade Ta/T1 with CIS should be within 12 months of last exposure to BCG and patients with Ta/T1 without CIS should be within 6 months of last exposure to BCG
   • No maximum limit to the amount of BCG administered
   • All visible papillary tumors must be resected and those with persistent T1 disease on transurethral resection of bladder tumor (TURBT) should undergo 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 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) are permitted to be in the study at the discretion of the investigator (see exclusion criterion 10).
10. Female patients 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 patients must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile. 'Maximally effective birth control' means that the patient, if sexually active, should be using a combination of two methods of birth control that are approved and recognized to be effective by Regulatory Agencies
11. Male patients 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
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 that increase the risk of metastatic disease are (but not limited to):

   • Presence of lymphovascular invasion and/micropapillary disease as shown in the histology of the biopsy sample
   • 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 can enter the study)
7. Clinically significant and unexplained elevated liver or renal function tests
8. Women who are pregnant or lactating or refuse to commit to use contraception anytime during the study
9. Any other significant disease or other clinical findings which in the opinion of the investigator would prevent study entry
10. History of malignancy of other organ system within 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 are under active surveillance are excluded (see inclusion criterion 9)
11. Patients who cannot hold instillation for 1 hour
12. Patients who cannot tolerate intravesical dosing or intravesical surgical manipulation

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 is permitted between 14 to 60 days prior to beginning study treatment
    • previous intravesical BCG therapy, which can be given at least 5 weeks before the diagnostic biopsy required for entry into the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02773849
• Other Study ID Numbers: rAd-IFN-CS-003
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ferring Pharmaceuticals
• Original Responsible Party: FKD Therapies Oy
• Current Study Sponsor: Ferring Pharmaceuticals
• Original Study Sponsor: FKD Therapies Oy

Collaborators

• FKD Therapies Oy
• Society of Urologic Oncology Clinical Trials Consortium

Investigators

• Principal Investigator: Stephen Boorjian, MD; Mayo Clinic

• PRS Account: Ferring Pharmaceuticals
• Verification Date: August 2023