RAD001 and Intravesical Gemcitabine in BCG-Refractory Primary or Secondary Carcinoma In Situ of the Bladder

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of gemcitabine applied to the bladder directly combined with different oral doses of everolimus and to assess the right doses. Gemcitabine will be given at a fixed dose. Up to 3 dose levels of everolimus will be evaluated. The purpose of the phase II part is to test the combination of gemcitabine applied to the bladder directly combined with different oral doses of everolimus and to study the effects of these two drugs together. The investigators want to find out what effects, good and/or bad, this treatment has on the patient and the cancer.

Official Title
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Phase I/II Study of RAD001 and Intravesical Gemcitabine in BCG-Refractory Primary or Secondary Carcinoma In Situ of the Bladder

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Everolimus and Intravesical Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have Bacille Calmette-Guérin (BCG) refractory primary or secondary TisN0M0 BCG-refractory disease is defined as: Patient positive for Cis after 2 consecutive BCG installations OR, patient had a BCG response and failure within 6 months OR, patient has Cis on maintenance BCG OR, patient has persistent Cis 6 months after at least one instillation of BCG OR, patient is BCG intolerant OR, any of the above criteria for patients with a history of T1 disease OR, patient has BCG-relapsing disease, defined as failure more than 6 months after the patient was disease-free Pathologic confirmation of urothelial carcinoma by the enrolling institution Karnofsky Performance Status (KPS) ≥ 70% Age ≥ 18 years Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL Adequate liver function as shown by: serum bilirubin ≤ 1.5 x ULN (upper limit of normal) ALT and AST ≤ 2.5x ULN International normalized ratio (INR) ≤1.5 x ULN (Anticoagulation is allowed if target INR ≤ 1.5 x ULN on a stable dose of warfarin or on a stable dose of low molecular weight (LMW) heparin for >2 weeks Adequate renal function: serum creatinine ≤ 1.5 x ULN Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid-lowering medication. After lipid-lowering therapy, patients must meet the same criteria, i.e. a fasting serum cholesterol < 300 mg/dL OR < 7.75 mmol/L AND fasting triglycerides < 2.5 x ULN, to be eligible for study treatment. Pre-treatment tumor tissue (minimum 10 slides) or 1 paraffin-embedded block when available for analysis of m-TOR pathway markers. Testing for hepatitis B viral load and serological markers (Hepatitis B PCR quantitative, HBsAg, HBsAb, and HBcAb) for the following patients: All patients who currently live in (or have lived in) Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, or Greece Patients with any of the following risk factors: Known or suspected past hepatitis B infection Blood transfusion(s) prior to 1990 Current or prior IV drug users Current or prior dialysis Household contact with hepatitis B infected person(s) Current or prior high-risk sexual activity Body piercing or tattoos Mother known to have hepatitis B History suggestive of hepatitis B infection, e.g. dark urine, jaundice, or right upper quadrant pain Additional patients at the discretion of the site Principal Investigator Testing for hepatitis C infection (using quantitative RNA-PCR) for patients with any of the following risk factors: Known or suspected past hepatitis C infection (including patients with past interferon curative treatment) Blood transfusion(s) prior to 1990 Current or prior IV drug users Household contact of hepatitis C infected person(s) Current or prior high-risk sexual activity Body piercing or tattoos Additional patients at the discretion of the site Principal Investigator Exclusion Criteria: Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.) with the exception of topical anti-neoplastic agents that are not being used to treat malignancy Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery or patients that may require major surgery during the course of the study. Prior treatment with any investigational drug within the preceding 4 weeks Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed. Patients should not receive immunization with attenuated live vaccines within 1 week of study entry or during study period Other malignancies within the past 3 years, except for adequately treated carcinoma of the cervix, basal or squamous cell carcinomas of the skin or adenocarcinoma of the prostate that has been treated. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: symptomatic congestive heart failure of New York Heart Association Class III or IV unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease Severely impaired lung function as defined by spirometry and diffusing capacity of lung for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN active (acute or chronic) or uncontrolled severe infections including urinary tract infections liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis A known history of HIV seropositivity Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Everolimus (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small-bowel resection) Patients with an active, bleeding diathesis Female patients who are pregnant or breast feeding, Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to administration of Everolimus. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment. High effective contraception methods include combination of any two of the following (a+b or a+c or b+c): Use of oral, injected or implanted hormonal methods of contraception or; Placement of an intrauterine device (IUD) or intrauterine system (IUS); Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository; Total abstinence or; Male/female sterilization. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to registration. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception during the study and for 8 weeks after the end of treatment. Patients with a known hypersensitivity to Everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients History of noncompliance to medical regimens Patients unwilling to or unable to comply with the protocol Prior radiation to the pelvis for bladder cancer

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: Pts who failed or relapsed after intravesical BCG<br>Phase I: Everolimus will be administered as follows: Dose level 1: 5 mg every other day, Dose level 2: 5 mg daily, Dose level 3: 10 mg daily Phase II: Everolimus will be administered at the dose determined in Phase .Everolimus will be continued for 12 months in the patients who achieve a CR or a Partial Response. Patients demonstrating a CR (by cystoscopy and cytology) or a Partial Response at their Cycle 12 cystoscopy will be observed with serial cystoscopies every 3 months. | Drug: Everolimus and Intravesical Gemcitabine<br>* Phase I: Everolimus will be adm as follows: Dose level 1: 5 mg every other day, Dose level 2: 5 mg daily, Dose level 3: 10 mg daily Phase II: Everolimus will be adm at 10 mg daily the dose determined in Phase I. Pts will receive a dose of 2000 mg of intravesical gemcitabine twice a week (72-96 +8 hours between doses) for 3 weeks for a total of 6 treatments in course 1. After 1 week of rest from intravesical gemcitabine, course 2 will be administered, provided the treating physician notes acceptable pt tolerance. The total number of intravesical instillations will be 12. There will be no dose modifications to gemcitabine; however, pts will be allowed to skip gemcitabine doses if needed, per the treating physician's discretion. Missed or skipped doses of gemcitabine will not be repeated. The pt will receive as many instillations as tolerable up to the maximum of 12 instillations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Dose-limiting Toxicity (DLT) | Everolimus (mg) given in conjunction with intravesical gemcitabine | 8 weeks | 
| Phase II - Patients Who Are Free of Disease at 1 Year | following start of therapy. | 1 year | 
| Phase I - Maximum Tolerated Dose (MTD) | of Everolimus given in conjunction with intravesical gemcitabine | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate | Complete Response (CR) is defined as no evidence of disease (by cytology and cystoscopy). Partial Response is defined as negative cystoscopy and positive cytology. Progression is defined as the development of invasion or metastasis. If the participant develops a recurrence, they will be considered having failed treatment. Participants will also be considered having failed treatment if there is no response to treatment after two cycles. | 1 year | 
| Survival of Patients Treated | With Everolimus in combination with intravesical gemcitabine. Overall survival following start of therapy will be estimated using Kaplan-Meier methods. | 1 year | 
| Activated mTOR (Mammalian Target of Rapamycin) Pathway Markers as Well as Phosphatase and Tensin Homolog (PTEN) Status and Serine/Threonine Kinase (AKT) Activation Evaluation | In all pre-treatment specimens and analysis of post treatment specimens when available. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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10-165, GEMCITABINE, RAD001(EVEROLIMUS), urinary, BCG-Refractory, Intravesical