A Study of Toca 511 & Toca FC in Patients With Recurrent High Grade Non-Muscle Invasive Bladder Cancer (Toca 8)
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Sequential Dose Cohorts 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
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.
Other Names:
Drug: Toca FC (extended-release formulation of flucytosine)
Toca FC is an extended-release formulation of flucytosine and is supplied as 500 mg tablets
Other Names:
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Outcome Measures
Primary Outcome Measures
- Dose-limiting toxicities [5 weeks]
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
Secondary Outcome Measures
- 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]
Other Outcome Measures
- Changes from baseline in immune activity in tumor, peripheral blood, and urine [21 weeks]
- Complete response rate at 6 and 12 months in patients with carcinoma in situ (CIS) [Proportion of patients with CIS with complete response at 6 and 12 months]
- High-grade recurrence-free survival [Event free survival overall and at 6 and 12 months]
- Incidence of cystectomy [The proportion of patients who undergo cystectomy]
- Incidence of disease progression at 6 and 12 months [The proportion of patients with disease progression at 6 and 12 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Provide written informed consent to participate
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At least 18 years of age
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Recurrent HG NMIBC, with HG tumor on previous histopathology
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Undergoing planned TURBT and biopsy of CIS suspicious areas
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No imaging findings consistent with T2 or greater disease, hydronephrosis, extravesical disease, nodal involvement, metastases, or other malignancies.
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Able and willing to wait at least 2 weeks following intravesical administration of Toca 511 to undergo TURBT
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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
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Patient is able to be catheterized and is anticipated to be able to retain Toca 511 for approximately 2 hours
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Estimated life expectancy of at least 12 months
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Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
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Patient has adequate organ function, as indicated by the following laboratory values
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Complete blood count: hemoglobin ≥ 10 g/dL, platelet count ≥ 100,000/mm3, absolute neutrophil count ≥ 1,500/ mm3, absolute lymphocyte count ≥ 500/ mm^3
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Liver: total bilirubin ≤ 1.5 × the upper limit of normal (ULN; unless known Gilbert's syndrome); alanine aminotransferase ≤ 2.5 × ULN
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Kidney: estimated glomerular filtration rate (GFR: Cockcroft-Gault) ≥ 50 mL/min
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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.
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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:
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History of urothelial cancer in the upper tract or urethra; muscle invasive bladder cancer; or metastatic bladder cancer
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History of bladder tumors other than urothelial carcinoma (ie, neuroendocrine, adenocarcinoma, or squamous cell carcinoma)
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Treatment with intravesical agents within 28 days prior to Toca 511 administration
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TURBT within 12 weeks prior to planned Toca 511 administration
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History of pelvic radiation
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Bladder tumor located within a bladder diverticulum
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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
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Severe lower urinary tract dysfunction clinically manifest as poor capacity, disabling incontinence, chronic catheter use, or chronic infections or stones
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Presence of suprapubic catheter
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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.)
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Active infection requiring antibiotic, antifungal, or antiviral therapy within 2 weeks prior to administration of Toca 511
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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
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Chronic treatment with autoimmune medications
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Human immunodeficiency virus (HIV) seropositive
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Pregnant or breast feeding
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Bleeding diathesis, or required to take anticoagulants or antiplatelet agents, including nonsteroidal anti-inflammatory drugs, that cannot be stopped for surgery
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Severe pulmonary, cardiac, or other systemic disease, specifically:
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New York Heart Association > Class II congestive heart failure that is not controlled on standard therapy within 6 months prior to Toca 511 administration
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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)
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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
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History of allergy or intolerance to flucytosine
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Presence of a condition that would prevent the patient from being able to swallow Toca FC tablets
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Tocagen Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Tg 511-19-01