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

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)

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.

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.

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