TriangleNCT02773849 · CITED IN SOURCE DOCUMENTS
ADSTILADRIN (=INSTILADRIN) in Patients With High-Grade, Bacillus Calmette-Guerin (BCG) Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- COMPLETED
- Registry last update
- 2024-07-29
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.
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What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
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.
Durability of Complete Response in Patients With CIS (With or Without Concomitant Ta or T1 Papillary Disease) Who Achieve a Complete Response.
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)
Durability of High-grade-recurrence-free Survival in Patients With High-grade Ta or T1 Papillary Disease (With or Without Concomitant CIS)
Incidence of Cystectomy at 12 Months, 2 Years and 5 Years
Overall Survival Rate in All Patients
Anti-adenoviral Antibody Levels for Correlation to Response Rate
Safety of ADSTILADRIN
Durability of Response During the Long-term Follow-up Period.
Adverse events
Limitations, agreements, and source contact
Who could take part
- 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
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- Intravesical administration of ADSTILADRIN into the bladder
- intervention Names
- Biological: ADSTILADRIN
- label
- ADSTILADRIN
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- ADSTILADRIN
- name
- ADSTILADRIN
- other Names
- rAd-IFN/SYN3NODA
- INSTILADRIN
- type
- BIOLOGICAL
Study design
- allocation
- NA
- intervention Model
- SINGLE_GROUP
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 157
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- 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.
- 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.
- time Frame
- 12 Months
- secondary Outcomes
- description
- 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.
- measure
- 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 57 months
- description
- 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.
- 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)
- time Frame
- up to 57 months
- description
- 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.
- measure
- Durability of High-grade-recurrence-free Survival in Patients With High-grade Ta or T1 Papillary Disease (With or Without Concomitant CIS)
- time Frame
- Up to 57 months
- description
- 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.
- measure
- Incidence of Cystectomy at 12 Months, 2 Years and 5 Years
- time Frame
- 60 Months
- description
- 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.
- measure
- Overall Survival Rate in All Patients
- time Frame
- 60 Months
- description
- 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.
- measure
- Anti-adenoviral Antibody Levels for Correlation to Response Rate
- time Frame
- 12 Months
- description
- The type, incidence, relatedness and severity of treatment emergent adverse events of ADSTILADRIN as assessed by NCI-CTCAE V4.03 were monitored.
- measure
- Safety of ADSTILADRIN
- time Frame
- 60 Months
- description
- 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.
- measure
- Durability of Response During the Long-term Follow-up Period.
- time Frame
- Up to 60 Months
Full study description
- 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.
Source references
- 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.
- pmid
- 33253641
- type
- RESULT
- citation
- Konety BR, Lotan Y, Myers A. Safety of nadofaragene firadenovec-vncg: review of data from phase 2 and phase 3 studies. Can J Urol. 2025 Mar 18;32(1):29-36. doi: 10.32604/cju.2025.064710.
- pmid
- 40194933
- type
- DERIVED
- citation
- Narayan VM, 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, Mashni J Jr, Lane BR, Guzzo TJ, Bratslavsky G, Karsh LI, Woods ME, Brown G, Canter D, Luchey A, Lotan Y, Inman BA, Williams MB, Cookson MS, Chang SS, Sankin AI, O'Donnell MA, Sawutz D, Philipson R, Parker NR, Yla-Herttuala S, Rehm D, Jakobsen JS, Juul K, Dinney CPN. Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guerin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial. J Urol. 2024 Jul;212(1):74-86. doi: 10.1097/JU.0000000000004020. Epub 2024 May 5.
- pmid
- 38704840
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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- 14 CLINICAL STUDIES The efficacy of ADSTILADRIN was evaluated in CS-003 (NCT02773849), an open-label, multicenter, single-arm trial in 103 adults with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ (CIS)
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Preserved source evidence · Not medical advice