Secondary Prevention Trial of Rapamycin in Patients With Resected Non-muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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The study is a multi-site Phase 3 double-blinded randomized placebo-controlled trial. Subjects are randomly assigned to receive either a placebo or oral Sirolimus: 0.5 mg daily. All subjects will be treated for 2 years or until disease recurrence. Patients will undergo endoscopic evaluation of the bladder every 3 months for the first 2 years following enrollment and then every 6 months for an additional 2 years on study. Selection of BCG immune therapy is at the discretion of the treating urologist but in general is reserved for high-risk patients. Patients concurrently receiving BCG immune therapy will receive standard BCG therapy including induction (weekly for 6 weeks) and maintenance (weekly for 3 weeks at 3 months, 6 months, and then every 6 months following tumor resection).

Official Title
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Secondary Prevention Trial of Rapamycin in Patients With Resected Non-muscle Invasive Bladder Cancer

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Rapamycin
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically) proven diagnosis of non-muscle invasive (Ta, Tis or T1) bladder cancer within 60 days prior to enrollment Be able to give informed consent Be age 18 or older Not be in an immunosuppressed state (e.g. HIV, use of chronic steroids) Not have active, uncontrolled infections Not be on agents known to alter rapamycin metabolism significantly Not have a reported history of liver disease (e.g. cirrhosis) Not have a prior history of non-bladder cancer unless the cancer is clinically stable and not requiring active treatment except basal cell carcinoma or squamous cell carcinoma of the skin. Not pregnant, or taking effective contraception before rapamycin therapy, during therapy and for 12 weeks after discontinuation of therapy. Exclusion Criteria: Have muscle-invasive (≥T2) bladder cancer Unable to give informed consent Age < 18 Immunosuppressed state (e.g. HIV, use of chronic steroids) Active, uncontrolled infections On agents known to alter rapamycin metabolism significantly Another cancer requiring active treatment (except basal cell carcinoma or squamous cell carcinoma of the skin) Patients at risk of pregnancy who are unwilling or unable to take effective contraception before rapamycin therapy, during therapy, and for 12 weeks after discontinuation of therapy. Individuals with a reported history of liver disease (e.g. cirrhosis)

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: When it is determined that you are eligible for the study, you will be assigned by chance (like flipping a coin) to one of 2 study groups. Sirolimus 0.5 mg/day for 2 years or until disease recurrence Placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Oral Tablet<br>Subject will be randomized to take the Placebo once daily for 2 years or until disease recurrence | Drug: Placebo Oral Tablet<br>* Subject will be randomized to one of the 2 arms<br>|
| Active Comparator: Sirolimus (Rapamycin) 0.5 mg/day for 2 years<br>Subject will be randomized to take Sirolimus (Rapamycin) 0.5mg once daily for 2 years or until disease recurrence | Drug: Rapamycin<br>* Subject will be randomized to one of the 2 arms<br>* Other names: Sirolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Test the hypothesis that rapamycin 0.5 mg daily increases recurrence-free survival for patients with non-muscle invasive bladder cancer | Recurrence is defined as histologically-proven bladder cancer (stage CIS, Ta, T1 or ≥T2) | Patients are treated for 2 years or until disease relapse | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine effects of rapamycin on recurrence-free survival (RFS) for subgroup of patients with non-muscle invasive bladder cancer concurrently receiving BCG immune therapy. | Recurrence is defined as histologically-proven bladder cancer (stage CIS, Ta, T1 or ≥T2) | Patients are treated for 2 years or until disease relapse | 
| To compare the effects of rapamycin on BCG-specific immunity during treatment of non-muscle invasive bladder cancer with maintenance BCG. | BCG antigen-specific IFN-gamma ELISPOT responses will be measured | baseline and 6 months after registration |