Trial of Encapsulated Rapamycin (eRapa) for Bladder Cancer Prevention

Study Overview
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Brief Summary
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eRapa (encapsulated rapamycin) will be investigated for secondary prevention in patients with diagnosed non-muscle invasive bladder cancer (NMIBC) through a phase II double-blind randomized controlled trial of long-term (one year) prevention with eRapa versus placebo. The primary hypothesis is that eRapa decreases the risk of cancer relapse for patients with NMIBC. Secondary hypotheses are that eRapa can improve certain immune parameters and improve cognition and physical function without adversely affecting patient-reported outcomes and quality of life.

Detailed Description
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The study is a multi-site phase II double-blind randomized trial. Subjects will be randomized into placebo arm or intervention arm with low dose (0.5 mg) eRapa (encapsulated rapamycin) Monday-Friday for one year or until disease recurrence. Patients will undergo endoscopic evaluation of the bladder every 3 months for 2 years, then every 6 months for 2 years, and at year 5. Some patients may also concurrently receive BCG immune therapy maintenance (weekly for 6 weeks for induction period, weekly for 3 weeks at 3 months, 6 months, and then every 6 months for a total of 7 maintenance cycles following tumor removal) per standard of care. Patient-reported outcome (PRO) assessments, cognitive assessments, and physical assessments will be completed according to the study calendar. Research blood to assess safety, immune response and rapamycin level will be collected regularly throughout the study period. Participants will be followed for up to 5 years following enrollment.

Official Title
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Phase II Trial of Encapsulated Rapamycin (eRapa) for Bladder Cancer Prevention

Conditions
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Non-muscle Invasive Bladder Cancer

Intervention / Treatment
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* Drug: eRapa
* Drug: Placebos


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 90 days prior to enrollment Able to give informed consent 18 years or older Patients must not be taking oral glucocorticoids at the time of registration Not have active, uncontrolled infections No other prior non-bladder malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years. Patients with localized prostate cancer who are being followed by an active survelillance program are also eligible. Patients must not be pregnant or nursing, as the use of Intravesical BCG is not recommended during pregnancy. Women/ men of reproductive potential must have agreed to use an effective contraceptive method. A woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months. Examples of effective contraception include hormonal contraception, double barrier method (condom with spermicidal cream, diaphragms with spermicidal cream, or condoms with diaphragms), Intrauterine device, and/or partner vasectomy. In addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Both male and female patients will be required to disclose contraception method during screening and agree to continue to use that contraception method through the end of their participation in the study. Patients must have had all grossly visible papillary tumors removed within 90 days prior to registration or cystoscopy confirming no grossly visible papillary tumors within 90 days prior to registration. Patients with T1 disease must have cross-sectional imaging of abdomen/pelvis demonstrating no evidence of nodal involvement or metastatic disease (MRI or CT scan) within 90 days prior to registration. Patients with T1 disease must have re-resection confirming ≤ T1 disease within 90 days prior to registration. Patients must no have received prior intravesical BCG Exclusion Criteria: Have muscle-invasive or higher (≥T2) bladder cancer Unable to give informed consent Age 17 or younger Taking oral glucocorticoids at the time of registration Another cancer requiring active treatment (except basal cell carcinoma or squamous cell carcinoma of the skin) Patients at risk of pregnancy that are unwilling or unable to take effective contraception during the study period, or patients that are nursing during the study period. Women/ Men of reproductive potential must have agreed to use an effective contraceptive method or will be considered ineligible for study participation. Evidence of nodal involvement or metastatic disease (MRI or CT scan) within 90 days prior to registration History of prior intravesical BCG History of prior Rapamycin treatment

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a multi-site phase II double-blind randomized trial. Subjects will be randomized into placebo arm or intervention arm with low dose (0.5 mg) eRapa (encapsulated rapamycin) Monday-Friday for one year or until disease recurrence. Patients will undergo endoscopic evaluation of the bladder every 3 months for 2 years, then every 6 months for 2 years, and at year 5. Some patients may also concurrently receive BCG immune therapy maintenance (weekly for 6 weeks for induction period, weekly for 3 weeks at 3 months, 6 months, and then every 6 months for a total of 7 maintenance cycles following tumor removal) per standard of care. Patient-reported outcome assessments, cognitive assessments, and physical assessments will be completed according to the study calendar. Research blood to assess safety, immune response and rapamycin level will be collected regularly throughout the study period. Participants will be followed for up to 5 years following enrollment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Study Drug Group<br>Patients will be given 0.5mg eRapa (encapuslated rapamycin) orally each weekday (Monday-Friday) for one year. | Drug: eRapa<br>* 0.5mg eRapa (encapsulated rapamycin) oral capsules<br>* Other names: encapsulated rapamycin;|
| Placebo Comparator: Placebo Group<br>Patients will be given a placebo (visually identical to the eRapa (encapsulated rapamycin)) orally each weekday (Monday-Friday) for one year. | Drug: Placebos<br>* placebo capsules visually identical to eRapa oral capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine 1-year Recurrence Free Survival (RFS) rate | The primary analysis will be the estimation of the RFS rate with the 95% confidence interval and comparison of the rate to the historical rate of 68% using the single arm log-rank test (one-sided alpha = 0.05). If the observed rate of RFS is 80% the expected number of events is about 20-28. Recurrence confirmed by pathologic examination of biopsied tissue. | 1 year | 
| Change in Urinary Quality of Life | Urinary Quality of Life measured using the urinary domain of the QLQ-BLS24 Index (a 24-item questionnaire that measures quality of life as it relates to urinary symptoms, sexual function, and bother domains). QLQ-BLS24 with a scale ranging from 24-96, and higher scores are worse. | Scored at baseline and months 3, 6, 12 and 24. For any subject who has a recurrence after enrollment, but prior to completing a full year of dosing at Visit 6, this will also be measured at the End of Treatment visit. | 
| Change in Cognitive Function | Cognitive function will be measured throughout the study period using EXIT. The EXIT is a brief 25-item interview that will be used by trained research staff to evaluate executive cognitive dysfunction of subjects. | EXIT will be scored at baseline and on months 12 and 24.For any subject who has a recurrence after enrollment, but prior to completing a full year of dosing at Visit 6, this will also be measured at the End of Treatment visit. | 
| Change in Cognitive Function | Cognitive function will be measured throughout the study period using St. Louis University Mental Status exam (SLUMS). The SLUMS exam will be used to evaluate memory, digit span and animal fluency. | SLUMS will be scored at baseline and on months 12 and 24.For any subject who has a recurrence after enrollment, but prior to completing a full year of dosing at Visit 6, this will also be measured at the End of Treatment visit. | 
| Change in Cognitive Function | Cognitive function will be measured throughout the study period using Texas Assessment of Processing Speed (TAPS). The TAPS test will evaluate digit/symbol coding. | TAPS will be scored at baseline and on months 6, 12, and 24. For any subject who has a recurrence after enrollment, but prior to completing a full year of dosing at Visit 6, this will also be measured at the End of Treatment visit. | 
| Change in cytoscopy consistent with recurrence (time to recurrence) | Change in cytoscopy results from baseline consistent with recurrence, confirmed by pathologic examination of biopsied tissue. | Patients will undergo office-based cystoscopy with urine cytology every 3 months for the first 2 years, then every 6 months for 2 years, and at year 5, with biopsies per standard of care if necessary. | 
| Change in Short Physical Performance Battery | The Short Physical Performance Battery (SPPB) consists of a balance test looking at the ability to maintain three standing positions for 10 seconds, a timed 4-meter walk in which subjects perform their walk at their preferred walking speed, and a chair stand test that times the ability of the subject to arise from a chair 5 times without using their arms. Each section is scored out of 4 points, for a total possible score of 12 points. This test provides information on several motor domains such as static and dynamic balance, coordination, and strength of lower limbs. Lower scores may be associated with increased disability risk. The SPPB and Handgrip Strength are physical assessments. | SPPB will be scored at baseline and on months 6, 12, and 24. For any subject who has a recurrence after enrollment, but prior to completing a full year of dosing at Visit 6, this will also be measured at the End of Treatment visit. | 
| Change in Handgrip Strength | When measuring handgrip strength, the subject will be seated in a chair with the forearm at a 90-degree elbow bend. Three consecutive grip strengths will be completed with a standard grip strength dynamometer for both hands. The Handgrip Strength and SPPB are physical assessments. | Handgrip Strength will be scored at baseline and on months 6, 12, and 24. For any subject who has a recurrence after enrollment, but prior to completing a full year of dosing at Visit 6, this will also be measured at the End of Treatment visit. |