Intravesical Ty21a for the Treatment of Patients With Non-muscle-invasive Bladder Cancer (NMIBC)

Study Overview
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Brief Summary
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Bladder cancer is the fourth and eighth most common malignancy among men and women, respectively. About 75% of bladder cancers are diagnosed as non muscle-invasive and according to specific tumor-stage and grade characteristics, intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) is used to prevent recurrence and/or progression. However, BCG immunotherapy is associated with significant adverse events and treatment failure may occur in 30-40% of cases, hence the necessity for alternative therapies. In an orthotopic MB49 mouse bladder cancer model, another bacterial vaccine (Ty21a/Vivotif) turned out to be more effective than BCG for inducing tumor regression and mice survival upon intravesical instillation; and potentially safer because Ty21a bacteria did not infect/persist in any mice tissues nor in human bladder explants or cell lines, in contrast to BCG. Ty21a/Vivotif has been used in the last 30 years in millions of individuals as an oral typhoid vaccine with a high safety record. In this phase I trial we will be testing the safety of intravesical administration of Ty21a and its effect on bladder immunity in non-muscle invasive bladder cancer (NMIBC) patients, for whom recommendation of BCG therapy is not mandatory.

Detailed Description
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Escalating doses of Ty21a/Vivotif® will be administered by the intravesical route to evaluate whether Ty21 may replace the standard BCG immunotherapy in NMIBC patients. The minimal starting dose will be instilled intravesically once a week for 4 weeks in 3 patients. If well tolerated, a 5-fold higher dose will be instilled 4-times in 3 other patients, and so on for a maximum of 4 doses to be tested. The maximal tolerated dose will then be administered to 3 new patients 6-times once a week. If 6 instillations are well tolerated, 7 additional patients will be included to receive 6 instillations with this maximal tolerated dose.

Official Title
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Intravesical Ty21a for the Treatment of Patients With Non-muscle-invasive Bladder Cancer (NMIBC)

Conditions
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Non Muscle Invasive Bladder Cancer

Intervention / Treatment
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* Biological: Ty21a


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with an intermediary or low risk of progression of bladder cancer (according to an EORTC score and clinical considerations) and thus not requiring BCG immunotherapy will be included after a transurethral resection of the bladder tumor (TURBT). Male and Female patients aged > 18yrs, with a Karnofsky performance status of 60% or more, sero-negative for HIV, HBV and HCV and with laboratory parameters for vital function in the normal range or with abnormalities without clinical significance may be included. Exclusion Criteria: Patients with NMIBC that require BCG treatments or with muscle-invasive bladder cancer, sero-positive for HIV, HBV and HCV or with other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders, autoimmune disease), will be excluded.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: non muscle invasive bladder cancer patient<br>intravesical instillation of Ty21a in patients not requiring BCG | Biological: Ty21a<br>* intravesical administration of Ty21a<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | safety and tolerability of intravesical Ty21a | 6 weeks |