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

Sponsor

Cardiff University (Other)

Overall Status

Completed

CT.gov ID

NCT01090466

Collaborator

(none)

Enrollment

Location

97.4

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer Transitional Cell Cancer of the Renal Pelvis and Ureter Urethral Cancer	Drug: cisplatin Drug: gemcitabine hydrochloride Drug: temsirolimus Other: pharmacological study	Phase 1/Phase 2

Detailed Description

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

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Feb 1, 2008

Actual Primary Completion Date :

Jan 1, 2010

Actual Study Completion Date :

Mar 16, 2016

Outcome Measures

Primary Outcome Measures

Safety (recommended phase II dose and dose-limiting toxicities) (phase I) []
Progression-free survival at 6 months (phase I) []

Secondary Outcome Measures

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) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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