Gemcitabine Hydrochloride, Cisplatin, and Temsirolimus 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