Sirolimus, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Bladder Cancer

PRIMARY OBJECTIVES:

I. To define the maximum-tolerated dose (MTD) of sirolimus (rapamycin) combined with
gemcitabine hydrochloride and cisplatin (GC). (Phase I)

II. To determine the pathologic complete response rate at cystectomy in patients with
localized, muscle invasive carcinoma of the bladder (clinical tumor [T]2-4, node [N]0 or N1).
(Phase II)

SECONDARY OBJECTIVES:

I. To assess the response rate to rapamycin combined with GC. (Phase I)

II. To assess effect of rapamycin with GC on deoxyribonucleic acid (DNA) damage surrogates in
cancer associated stroma compared to untreated and GC treated stroma. (Phase I)

III. To assess effect of rapamycin with GC on DNA damage surrogates in cancer associated
stroma compared to untreated and GC treated stroma. (Phase II)

IV. To assess toxicity of the MTD dose of rapamycin with GC. (Phase II)

OUTLINE: This is a phase I, dose de-escalation study of sirolimus followed by a phase II
study.

Patients receive sirolimus orally (PO) two hours before or after grapefruit juice on day -2,
cisplatin intravenously (IV) on day 1 and gemcitabine hydrochloride IV over 30 minutes on
days 1 and 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity. Patients undergo cystectomy as clinically appropriate
after 1-4 courses of treatment.

After completion of study treatment, patients are followed up for 28 days.

Inclusion Criteria:

- Signed informed consent form (ICF) providing agreement to adhere to the dosing
schedule, report for all trial visits and authorization, use and release of health and
research trial information

- Histologically or cytologically confirmed carcinoma of the bladder of all histologies
except neuroendocrine differentiation or squamous cell histology

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

- Eligibility for phase 1 and phase 2 components:

- Phase 1 - clinical T3 or T4 or N1 or M1 cancer which is untreated or previously
treated with platinum based therapy with primary tumor still present in the
bladder and amenable to sampling before and after treatment, as indicated

- Phase 2 - clinical T2-4 N0 or N1 untreated with primary tumor still present in
the bladder and amenable to sampling before and after treatment, as indicated

- Life expectancy >= 12 weeks

- No prior malignancy is allowed except:

- Adequately treated basal cell or squamous cell skin cancer or

- In situ carcinoma of any site or

- Other adequately treated malignancy for which the patient is currently disease
free for at least one year

- Absolute neutrophil count >= 1.5 x 10^9 cells/L

- Hemoglobin (Hgb) >= 9.0 g/dL

- Platelets >= 100,000 x 10^9/L

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 1.5 x upper limit
of normal (ULN)

- Bilirubin and total bilirubin levels =< 1.5 x ULN

- Serum creatinine < 1.5 X institutional ULN mg/dL OR glomerular filtration rate (GFR)
>= 50 mL/min

- All pre-study labs required for determination of eligibility are to be completed
within 30 days prior to day -2 (or the next business day if falls on a weekend or
holiday)

- X-rays and/or scans to assess all disease sites are to be completed within 30 days
prior to day -2 (or the next business day if falls on a weekend or holiday)

Exclusion Criteria:

- Patients currently receiving active therapy for other neoplastic disorders

- Known parenchymal brain metastasis

- Active or symptomatic viral hepatitis or chronic liver disease

- Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or New
York Heart Association (NYHA) class II-IV heart disease or cardiac ejection fraction
measurement of < 45 % at baseline, if done

- Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy

- Administration of an investigational therapeutic within 30 days of cycle 1, day 1

- Patients with dementia/psychiatric illness/social situations that would limit
compliance with study requirements or would prohibit the understanding and/or giving
of informed consent

- Patients with medical conditions, which, in the opinion of the investigators, would
jeopardize either the patient or the integrity of the data obtained will not be
eligible

- Any condition which, in the opinion of the investigator, would preclude participation
in this trial