Gemcitabine Hydrochloride, Cisplatin, and Temsirolimus as First-Line Therapy in Treating Patients With Locally Advanced and/or Metastatic Transitional Cell Cancer of the Urothelium

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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A Phase I/II Single-Arm Trial to Evaluate the Combination of Cisplatin and Gemcitabine With the mTOR Inhibitor Temsirolimus for First-Line Treatment of Patients With Advanced Transitional Cell Carcinoma of the Urothelium

Conditions
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Bladder Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Urethral Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: gemcitabine hydrochloride
* Drug: temsirolimus
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 120 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

| Intervention/Treatment |
| --- |
|Drug: cisplatin|nan|
|Drug: gemcitabine hydrochloride|nan|
|Drug: temsirolimus|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (recommended phase II dose and dose-limiting toxicities) (phase I) |  |  | 
| Progression-free survival at 6 months (phase I) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (phase I) |  |  | 
| Safety, including tolerability and feasibility (phase II) |  |  | 
| Overall survival (phase II) |  |  | 
| Progression-free survival (time-to-event) (phase II) |  |  | 
| Objective (radiological) response rate according to RECIST criteria (phase II) |  |  | 
| Toxicity during and after treatment according to NCI CTCAE v 3.0 (phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transitional cell carcinoma of the bladder, recurrent bladder cancer, recurrent urethral cancer, recurrent transitional cell cancer of the renal pelvis and ureter, stage IV bladder cancer, metastatic transitional cell cancer of the renal pelvis and ureter, regional transitional cell cancer of the renal pelvis and ureter, distal urethral cancer, proximal urethral cancer, urethral cancer associated with invasive bladder cancer, stage IV urethral cancer