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

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