A Study Testing a New Drug (ALT-803) With BCG to Treat Early-Stage Bladder Cancer

Prior treatment

• Patients with ANY of the following criteria are excluded from participation in the study: 1. Prior BCG treatment in the last 3 years or known hypersensitivity to BCG or known history of BCG Unresponsive NMIBC. Patients who have received more than a single-dose post-operative treatment of mitomycin-C or gemcitabine following the most recent screening TURBT/biopsy are excluded. 2. Concurrent use of other investigational agents (not including FDAauthorized drugs for the prevention and treatment of COVID-19). 3. History of or evidence of muscle-invasive, locally advanced, metastatic and/or extravesical bladder cancer or any other cancer within the past 5 years, except: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage 1 or 2 cancer from which the patient is currently in complete remission, or stable prostate cancer (under active surveillance or hormone control). 4. Symptomatic congestive heart failure (CHF), NYHA (New York Heart Association) Class III or IV (Appendix 16.4) or other clinical signs of severe cardiac dysfunction. 5. Severe/unstable angina pectoris, or myocardial infarction within 6 months prior to study entry. 6. History or evidence of uncontrollable central nervous system (CNS) disease. 7. Active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy. 8. Concurrent febrile illness, active urinary tract infection, active tuberculosis, a history of hypotension or anaphylactic reaction to BCG or N-803. 9. Ongoing chronic systemic steroid therapy required (>10 mg oral prednisone daily or equivalent). 10. Women who are pregnant or nursing. Female patients 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 and for 90 days post last dose of study drug. 11. Psychiatric illness/social situations that would limit compliance with study requirements. 12. Other illness that in the opinion of the Investigator would exclude the patient from participating in this study.

• Patients must meet ALL of the following criteria for inclusion in the study: 1. Histologic confirmation of non-muscle invasive bladder cancer of the transitional cell carcinoma high-grade subtype (mixed histology tumors allowed if transitional cell histology is predominant histology). a. Cohort A: Histologically confirmed CIS (with or without Ta/T1 disease); Cohort B: Histologically confirmed high-grade papillary disease (Ta/T1 only). b. Patients are eligible if the diagnostic biopsy was done within 3 months of treatment start and a cystoscopy demonstrating no resectable disease within 90 days of treatment start (residual CIS is acceptable; patients with T1 disease must undergo repeat resection if muscularis propria is not present in each biopsy sample). Patients with high-grade Ta and/or T1 disease should have complete resection before study treatment. If a repeat biopsy is required for any reason, a negative result does not exclude the patient, provided bladder cancer was confirmed in the initial diagnosis. c. Upper tract imaging within 6 months prior to study entry must not be suspicious for upper tract malignancy. 2. Currently eligible for intravesical BCG therapy. 3. Age ≥ 18 years. 4. Performance status: ECOG performance status of 0, 1, or 2. 5. BCG-naive disease as defined as either of the following: a. Have not received prior intravesical BCG; or b. Previously received BCG, but stopped receiving more than 3 years before date of randomization. 6. Laboratory tests performed within 21 days of treatment start: a. Absolute lymphocyte count ≥ Institutional lower limit of normal b. Absolute neutrophil count (AGC/ANC) ≥ 1,000/µL c. Platelets ≥ 100,000/µL [Patients may be transfused to meet this requirement] d. Hemoglobin ≥ 8 g/dL [Patients may be transfused to meet this requirement] e. Calculated glomerular filtration rate (GFR*) >40 mL/min or Serum creatinine ≤ 1.5 x ULN f. Total bilirubin ≤ 2.0 X ULN g. AST, ALT, ALP ≤ 3.0 X ULN * using the following Cockcroft-Gault equation to calculate the eGFR for this study: eGFR in mL/min = {(140-age in years) x (weight in kg) x F}/(serum creatinine in mg/dL x 72) Where F =1 if male; and 0.85 if female 7. Adequate pulmonary function without any clinical sign of severe pulmonary dysfunction. PFT > 50% FEV1 if clinically indicated by the Investigator. 8. Negative serum pregnancy test if female and of childbearing potential (non-childbearing is defined as greater than one year postmenopausal or surgically sterilized). 9. Female participants of childbearing potential must adhere to using a medically accepted method of birth control prior to screening and agree to continue its use during the study or be surgically sterilized (eg, hysterectomy or tubal ligation) and males must agree to use barrier methods of birth control while on study. 10. Provide signed informed consent and agree to comply with all protocol-specified procedures and follow-up evaluations.