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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Bladder Cancer
• Intervention / Treatment: Biological: Toca 511; Drug: Toca FC (extended-release formulation of flucytosine)

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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: vocimagene amiretrorepvec; retroviral replicating vector (RRV); 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: flucytosine; 5-fluorocytosine (5-FC)

What is the study measuring?

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	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

Other Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Tocagen Inc.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2019
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): January 1, 2027

Study Registration Dates

• First Submitted: August 30, 2019
• First Submitted That Met QC Criteria: September 11, 2019
• First Posted (Actual): September 13, 2019

Study Record Updates

• Last Update Posted (Actual): March 30, 2020
• Last Update Submitted That Met QC Criteria: March 26, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: bladder cancer; NMIBC; non-muscle invasive bladder cancer; high grade non-muscle invasive bladder cancer; HG NMIBC; high grade NMIBC
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Antifungal Agents; Flucytosine
• Other Study ID Numbers: Tg 511-19-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No