Gemcitabine Hydrochloride, Cisplatin, and Temsirolimus as First-Line Therapy in Treating Patients With Locally Advanced and/or Metastatic Transitional Cell Cancer of the Urothelium
Gemcitabine Hydrochloride, Cisplatin, and Temsirolimus as First-Line Therapy in Treating Patients With Locally Advanced and/or Metastatic Transitional Cell Cancer of the Urothelium
RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work
 in different ways to stop the growth of tumor cells, either by killing the cells or by
 stopping them from dividing. Temsirolimus may stop the growth of tumor cells by blocking some
 of the enzymes needed for cell growth. Giving gemcitabine hydrochloride and cisplatin
 together with temsirolimus may kill more tumor cells.

 PURPOSE: This phase I/II trial is studying the side effects and best dose of temsirolimus
 given together with gemcitabine hydrochloride and cisplatin as first-line therapy in treating
 patients with locally advanced and/or metastatic transitional cell cancer of the urothelium.
OBJECTIVES:

 Primary

 -  To determine a safety profile of temsirolimus in combination with cisplatin and
 gemcitabine hydrochloride, including dose-limiting toxicities (DLTs) and
 maximum-tolerated dose (MTD) in patients with locally advanced and/or metastatic
 transitional cell carcinoma of the urothelium. (phase I)

 -  To determine the recommended dose for the Phase II stage of the trial and subsequent
 studies. (phase I)

 -  To assess progression-free survival (PFS) at six months from date of enrollment. (phase
 II)

 Secondary

 -  To determine the pharmacokinetic profile of temsirolimus in combination with cisplatin
 and gemcitabine hydrochloride. (phase I)

 -  To determine tolerability (side-effects) and feasibility (number of participants
 requiring dose delays or reduction and/or treatment withdrawal). (phase II)

 -  To determine objective response rate as assessed by RECIST. (phase II)

 -  To assess PFS of these patients. (phase II)

 -  To assess overall survival of these patients. (phase II)

 -  To determine toxicity during and after treatment in these patients. (phase II)

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

 Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, cisplatin IV
 over 3-4 hours on day 1, and temsirolimus IV over 30 minutes on days 1 or 2, 8 or 9, and 15.
 Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or
 unacceptable toxicity.

 Blood specimens may be collected periodically for pharmacokinetic studies.

 After completion of study treatment, patients are followed at 6 months and 1 year.

 Peer Reviewed and Funded or Endorsed by Cancer Research UK
DISEASE CHARACTERISTICS:

 -  Histologically confirmed transitional cell carcinoma of the urothelium

 -  Pure or mixed histology

 -  Upper or lower urinary tract

 -  Radiologically evaluable* locally advanced and/or metastatic disease not amenable to
 curative treatment with surgery or radiotherapy, meeting any 1 of the following
 criteria:

 -  T4b, any N, any M

 -  Any T, N2-3, any M

 -  Any T, any N, M1

 -  NOTE: *Patients enrolled in the phase II portion of the trial must have radiologically
 measurable disease.

 -  No transitional cell cancer for which subsequent radical treatment is being considered
 with a view to possibly cure the disease

 -  No history of CNS metastases

 PATIENT CHARACTERISTICS:

 -  WHO performance status 0-2

 -  Life expectancy ≥ 3 months

 -  Absolute neutrophil count ≥ 1.5 x 10^9/L

 -  Platelet count ≥ 100 x 10^9/L

 -  Bilirubin ≤ 1.5 times upper limit of normal (ULN)

 -  ALT and ALP ≤ 2.5 times ULN

 -  PT or INR ≤ 1.5

 -  GFR ≥ 60 mL/min (uncorrected for surface area and measured by isotopic means)

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  Fit to receive cisplatin-containing combination chemotherapy

 -  No previous malignancy other than nonmelanoma skin cancer, carcinoma in situ of the
 cervix, or incidental localized prostate cancer

 -  No known HIV positivity or chronic hepatitis B or C infection

 -  No symptomatic coronary artery disease, myocardial infarction within the past 6
 months, congestive cardiac failure (NYHA class III or IV disease), or uncontrolled or
 symptomatic cardiac arrhythmia

 -  No clinically significant bacterial or fungal infection

 PRIOR CONCURRENT THERAPY:

 -  At least 1 month since prior radiotherapy or radiotherapy involving more than 30% of
 total bone marrow volume

 -  At least 1 month since prior investigational drug

 -  No prior systemic therapy for locally advanced or metastatic disease

 -  Patients who have received prior neoadjuvant or adjuvant chemotherapy for
 urothelial cancer (up to 4 courses), completed at least 6 months prior to first
 documented disease progression are eligible

 -  No concurrent anticoagulant therapy with warfarin or unfractionated heparin

 -  Patients requiring anticoagulation may be entered on study after successful
 conversion to low molecular weight heparin

 -  No concurrent medications which have known adverse interactions with the treatment
 used on this trial (e.g., CYP3A4 inhibitors or inducers in phase I of this trial)

 -  No prior or concurrent live vaccines (e.g., measles, mumps, rubella, oral polio,
 Bacille Calmette-Guérin [BCG], yellow fever, varicella, and TY21a typhoid vaccines)

 -  No concurrent grapefruit juice