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

February 2, 2018 updated by: Cardiff University

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

15

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • England
      • Leeds, England, United Kingdom, LS9 7TF
        • Leeds Cancer Centre at St. James's University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 120 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Overall survival (phase II)
Pharmacokinetics (phase I)
Safety, including tolerability and feasibility (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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cardiff University

Investigators

  • Principal Investigator: John Chester, Leeds Cancer Centre at St. James's University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2008

Primary Completion (Actual)

January 1, 2010

Study Completion (Actual)

March 16, 2016

Study Registration Dates

First Submitted

March 18, 2010

First Submitted That Met QC Criteria

March 18, 2010

First Posted (Estimate)

March 22, 2010

Study Record Updates

Last Update Posted (Actual)

February 6, 2018

Last Update Submitted That Met QC Criteria

February 2, 2018

Last Verified

February 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000667766
  • WCTU-TOTEM
  • ISRCTN31546330
  • EUDRACT-2007-007615-82
  • EU-21014
  • WCTU-SPON-417-07
  • CRUK-08/015

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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