Sponsor decision

This is an open-label, randomized, phase 3 study of intravesical BCG plus ANKTIVA (experimental arm) versus BCG alone (control arm) in participants who have histologically confirmed, BCG-naïve/BCG-exposed high-grade Ta/T1 papillary disease. The purpose of this study is to evaluate the contribution of effect of neoadjuvant ANKTIVA plus BCG experimental therapy in papillary NMIBC.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

3. Histologic confirmation of NMIBC of the urothelial carcinoma HG subtype (mixed histology tumors allowed if transitional cell histology is predominant histology), including histologically confirmed presence of HG Ta or T1 papillary disease only.

4. No concurrent CIS at TURBT #1 during screening.

5. Visually complete TURBT #1 per Investigator.

6. BCG-naive disease, defined as either of the following:

   1. Have not received prior intravesical BCG; or
   2. Previously received BCG but stopped receiving more than 3 years before date of randomization.

7. BCG-exposed disease, defined as patients who have received at least 1 dose of BCG and do not meet the BCG-unresponsive criteria.

8. Agreement to practice effective contraception for female participants of child-bearing potential and non-sterile males. Female participants of child-bearing potential must agree to use effective contraception for up to 1 year after completion of therapy, and non-sterile male participants must agree to use a condom for up to 4 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, and intrauterine devices (IUDs).

9. Voluntary written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization and agree to comply with all protocol-specified procedures and follow-up evaluations.

Exclusion Criteria:

1. Life expectancy < 2 years.

2. BCG-unresponsive disease, defined as:

   1. Persistent or recurrent CIS (± recurrent Ta/T1 disease) within 12 months of receiving adequate BCG (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course); or
   2. Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course); or
   3. T1 high-grade disease at the first evaluation following an induction BCG course alone (at least 5 of 6 doses of an initial induction course)

3. Urinary tract infection or urinary retention.

4. Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder (that is, urethra, ureter, or renal pelvis/calyces). Ta/any T1/CIS of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephroureterectomy more than 24 months prior to randomization.

5. Presence of any bladder or urethral anatomic feature (example, urethral stricture) that, in the opinion of the Investigator, may prevent the safe administration of intravesical N-803 or BCG. Participants with tumors involving the prostatic urethra in men will be excluded.

6. History of clinically significant polyuria with recorded 24-hour urine volumes greater than 4000 milliliters (mL).

7. Indwelling catheters are not permitted; however, intermittent catheterization is acceptable.

8. History of or evidence of muscle-invasive, locally advanced, metastatic and/or extravesical bladder cancer (inclusive of prostatic urethra); or any other cancer within the past 5 years that is progressing or requires active treatment. Exceptions are adequately treated basal cell or squamous cell skin cancer that has undergone potentially curative therapy or in situ cervical cancer; and adequately treated stage I or II cancer or stable prostate cancer from which the participant is currently in complete remission and is under active surveillance.

9. Receiving investigational or commercial anticancer agents or anticancer therapies other than supportive care therapies for active disease within 28 days of enrollment.

10. Concurrent use of other investigational agents.

11. Concurrent febrile illness, active tuberculosis, a history of hypotension of anaphylactic reactions.

12. Ongoing chronic systemic steroid therapy required (> 10 mg prednisone daily or equivalent).

13. Women who are pregnant and nursing. Female participants of childbearing potential must have a negative pregnancy test and must adhere to using a medically acceptable method of birth control prior to screening and agree to continue its use during the study and for 30 days after the last dose of study drug, or be surgically sterilized (eg, hysterectomy or tubal ligation). Women of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Males must agree to use barrier methods of birth control while on study for 90 days post last dose of study drug.

14. Other illnesses or conditions, including laboratory abnormalities, which in the opinion of the Investigator would exclude the participant from participating in this study. This includes, but is not limited to, serious medical conditions or psychiatric illness likely to interfere with participation in the study.