Sponsor decision.

This is a Phase 1, multicenter, open-label study of intravesical Toca 511 followed by oral Toca FC in patients with high grade (HG) non-muscle invasive bladder cancer (NMIBC), with cohort expansion at the recommended Phase 2 dose. Patients with recurrent HG NMIBC who are undergoing planned transurethral resection of bladder tumor (TURBT) will be enrolled into the study, subject to meeting all entry criteria.

Inclusion Criteria:

• Provide written informed consent to participate

• At least 18 years of age

• Recurrent HG NMIBC, with HG tumor on previous histopathology

• Undergoing planned TURBT and biopsy of CIS suspicious areas

• No imaging findings consistent with T2 or greater disease, hydronephrosis, extravesical disease, nodal involvement, metastases, or other malignancies.

• Able and willing to wait at least 2 weeks following intravesical administration of Toca 511 to undergo TURBT

• If patient is a candidate for standard of care (SOC) intravesical therapy, able and willing to wait at least 2 weeks post-TURBT for initiation of such treatment

• Patient is able to be catheterized and is anticipated to be able to retain Toca 511 for approximately 2 hours

• Estimated life expectancy of at least 12 months

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

• Patient has adequate organ function, as indicated by the following laboratory values

  • Complete blood count: hemoglobin ≥ 10 g/dL, platelet count ≥ 100,000/mm^3, absolute neutrophil count ≥ 1,500/ mm^3, absolute lymphocyte count ≥ 500/ mm^3
  • Liver: total bilirubin ≤ 1.5 × the upper limit of normal (ULN; unless known Gilbert's syndrome); alanine aminotransferase ≤ 2.5 × ULN
  • Kidney: estimated glomerular filtration rate (GFR: Cockcroft-Gault) ≥ 50 mL/min

• Women of childbearing potential (defined as not postmenopausal [ie, ≥ 12 months of non-therapy-induced amenorrhea] or not surgically sterile) must have a negative serum pregnancy test within 7 days prior to administration of Toca 511, and be willing to use an effective means of contraception in addition to barrier methods (condoms) for the duration of the study.

• Patient and partner are willing to use condoms for 12 months after receiving Toca 511 and/or 30 days after the last dose of Toca FC, and/or until there is no evidence of the virus in his/her blood or urine, whichever is longer.

Exclusion Criteria:

• History of urothelial cancer in the upper tract or urethra; muscle invasive bladder cancer; or metastatic bladder cancer

• History of bladder tumors other than urothelial carcinoma (ie, neuroendocrine, adenocarcinoma, or squamous cell carcinoma)

• Treatment with intravesical agents within 28 days prior to Toca 511 administration

• TURBT within 12 weeks prior to planned Toca 511 administration

• History of pelvic radiation

• Bladder tumor located within a bladder diverticulum

• Genitourinary procedures (eg, prostate surgery; treatment of ureteral stones or moderate to extensive urethral stricture disease) prior to, during, or planned within the 4 weeks following TURBT, other than procedures for treatment of bladder tumors

• Severe lower urinary tract dysfunction clinically manifest as poor capacity, disabling incontinence, chronic catheter use, or chronic infections or stones

• Presence of suprapubic catheter

• History of other malignancy, unless the patient has been disease-free for at least 5 years. Adequately treated basal cell carcinoma or squamous cell skin cancer is acceptable regardless of time, as well as cervical carcinoma in situ or localized prostate carcinoma, after curative treatment. (Note: Men with very low or low risk prostate cancer on active surveillance are acceptable candidates for this study.)

• Active infection requiring antibiotic, antifungal, or antiviral therapy within 2 weeks prior to administration of Toca 511

• Investigational treatment within 2 weeks or immunotherapy or antibody therapy within 28 days prior to Toca 511 administration, and/or has not recovered from toxicities associated with such treatment

• Chronic treatment with autoimmune medications

• Human immunodeficiency virus (HIV) seropositive

• Pregnant or breast feeding

• Bleeding diathesis, or required to take anticoagulants or antiplatelet agents, including nonsteroidal anti-inflammatory drugs, that cannot be stopped for surgery

• Severe pulmonary, cardiac, or other systemic disease, specifically:

  • New York Heart Association > Class II congestive heart failure that is not controlled on standard therapy within 6 months prior to Toca 511 administration
  • Uncontrolled or significant cardiovascular disease, clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes), clinically significant pulmonary disease (such as ≥ Grade 2 dyspnea)
  • Any other serious medical, social, or psychological condition that, based on Investigator assessment, may affect the patient's compliance or place the patient at an increased risk of potential treatment complications

• History of allergy or intolerance to flucytosine

• Presence of a condition that would prevent the patient from being able to swallow Toca FC tablets