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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Superficial Bladder Cancer

Intervention / Treatment
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* Biological: ADSTILADRIN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older at the time of consent Able to give informed consent 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 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. Available for the whole duration of the study Life expectancy >2 years, in the opinion of the investigator Eastern Cooperative Oncology Group (ECOG) status 2 or less 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 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). 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 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 Adequate lab values Exclusion Criteria: 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 Current systemic therapy for bladder cancer Current or prior pelvic external beam radiotherapy within 5 years of entry Prior treatment with adenovirus-based drugs Suspected hypersensitivity to IFN alfa2b Symptomatic urinary tract infection or bacterial cystitis (once satisfactorily treated, patients can enter the study) Clinically significant and unexplained elevated liver or renal function tests Women who are pregnant or lactating or refuse to commit to use contraception anytime during the study Any other significant disease or other clinical findings which in the opinion of the investigator would prevent study entry 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) Patients who cannot hold instillation for 1 hour Patients who cannot tolerate intravesical dosing or intravesical surgical manipulation 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADSTILADRIN<br>Intravesical administration of ADSTILADRIN into the bladder | Biological: ADSTILADRIN<br> <br> * Other names: INSTILADRIN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durability of Complete Response in Patients With CIS (With or Without Concomitant Ta or T1 Papillary Disease) Who Achieve a Complete Response. | 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. | Up to 60 months | 
| 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) | 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. | up to 60 months | 
| 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. | 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. | Up to 60 months | 
| Incidence of Cystectomy in the Study | The incidence of and time to cystectomy will be measured in the study | 60 Months | 
| Overall Survival in All Patients | The incidence of and time to survival will be measured in the study | 60 Months | 
| Anti-adenoviral Antibody Levels for Correlation to Response Rate | 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. | 12 Months | 
| Safety of ADSTILADRIN | The type, incidence, relatedness and severity of treatment emergent adverse events of ADSTILADRIN as assessed by NCI-CTCAE V4.03 will be monitored. | 60 Months | 
| Durability of Response During the Long Term Follow up Period. | 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. | 60 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IFN, BCG-unresponsive, Non-Muscle Invasive Bladder Cancer (NMIBC)