A Study of Toca 511 & Toca FC in Patients With Recurrent High Grade Non-Muscle Invasive Bladder Cancer (Toca 8)

Study Overview
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Brief Summary
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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.

Official Title
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Toca 8: A Multicenter, Open-Label, Phase 1 Study to Evaluate the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Combined With Toca FC in Patients With Recurrent High Grade Non-Muscle Invasive Bladder Cancer

Conditions
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Bladder Cancer

Intervention / Treatment
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* Biological: Toca 511
* Drug: Toca FC (extended-release formulation of flucytosine)


Participation Criteria
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Eligibility Criteria
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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

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: Sequential Assignment
Interventional Model Description: 3+3 dose escalation design with expansion at recommended Phase 2 dose.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequential Dose Cohorts<br>Doses of Toca 511 will be evaluated in sequential cohorts. Toca 511 will be administered as a single intravesical instillation. Following Toca 511 administration, Toca FC will be administered orally at a dose of 220 mg/kg/day for 7 days every 6 weeks. | Biological: Toca 511<br>* Toca 511 consists of a purified retroviral replicating vector encoding a modified yeast cytosine deaminase (CD) gene. The CD gene converts the antifungal drug, flucytosine (5-fluorocytosine; 5-FC) to the anticancer drug 5-fluorouracil (5-FU) in cancer cells that have been infected by the Toca 511 vector.<br>* Other names: retroviral replicating vector (RRV);Drug: Toca FC (extended-release formulation of flucytosine)<br>* Toca FC is an extended-release formulation of flucytosine and is supplied as 500 mg tablets<br>* Other names: 5-fluorocytosine (5-FC);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities | Any treatment-related Grade 3 or higher non-hematologic toxicity, excluding nausea, vomiting, or diarrhea that are controllable with appropriate medical measures (eg, antiemetics, antimotility drugs) Any treatment-related Grade 4 or higher hematologic toxicity | 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in viral transduction of Toca 511 at each dose level, based on quantitation of viral RNA and DNA in tumor |  | 3 weeks (+/- 1 week) | 
| Clearance of viral RNA in plasma and urine, based on real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), and of viral DNA in whole blood and urine, based on quantitative PCR (qPCR) |  | 1 week for plasma, 4 weeks for urine | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-muscle invasive bladder cancer, bladder cancer, high grade non-muscle invasive bladder cancer, HG NMIBC, NMIBC, high grade NMIBC