Condition category
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

Contact information



Primary contact

Dr John Chester


Contact details

Cancer Research UK Clinical Centre
St. James’'s University Hospital
Beckett Street
United Kingdom
+44 (0)113 343 8434

Additional identifiers

EudraCT number

2007-007615-82 number


Protocol/serial number

SPON 417-07; C7838/A9346

Study information

Scientific 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 carcinoma of the urothelium



Study hypothesis

The prognosis for patients with advanced urothelial cancer (predominantly bladder) is poor and approximately 4,700 patients in the United Kingdom (UK) die each year from the disease. Approximately 50% of patients who are fit enough to undergo cisplatin-based chemotherapy will respond to treatment. Median progression-free survival for such patients is approximately 8 months and median overall survival 14 months. Despite a recent increase in our understanding of the molecular basis of bladder cancer, there have been few clinical studies using molecularly-targeted compounds in advanced urothelial cancer.

Temsirolimus (Torisel®) is a treatment which prevents the growth of tumours and has recently been demonstrated to improve survival in advanced renal cancer. Further studies suggest that temsirolimus may also have activity against urothelial cancer.

This trial will assess whether adding temsirolimus to the standard cisplatin/gemcitabine based chemotherapy in the treatment of advanced urothelial cancer is safe and effective and improves outcome of patients with advanced urothelial disease.

Ethics approval

Protocol approval will be sought from a Multicentre Research Ethics Committee (MREC). Each participating centre will be approved through a Regional Ethics Committee (REC) prior to patient recruitment.

Study design

Early phase I/II single-arm non-randomised open-label multicentre trial

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Locally advanced and/or metastatic transitional cell carcinoma of the urothelium


Patients will be recruited over approximately 18 months. All patients will receive a maximum of six 21-day cycles of cisplatin and gemcitabine chemotherapy in combination with temsirolimus. All three drugs will be administered intravenously.

The starting doses of cisplatin and gemcitabine will be fixed (70 mg/m^2, day one and 1000 mg/m^2 days one and eight, respectively); the optimum dose for temsirolimus will be determined in the phase I stage of the trial by dose-escalation in successive cohorts of three to six patients, until the maximum tolerated dose (MTD) is met. Intra-patient dose escalation will not be permitted. The recommended phase II dose will then be given to an expanded group of patients in the phase II stage.

A maximum of 18 patients will participate in phase I. In phase II, additional patients will be treated up to a total of 63 evaluable patients. Three or six patients treated at the MTD in phase I will be included in this total. The maximum number of patients that will be treated in the entire trial is therefore 78 patients.

Assessments will be performed at baseline, at specified times during trial treatment, and at 6 and 12 months from date of enrolment, as per timelines specified in the trial protocol, and including:
1. Diagnostic biopsy (in absence of previous histological diagnosis only)
2. Cross-sectional imaging (CT scan of chest, abdomen and pelvis)
3. Physical exam (including height and weight)
4. WHO performance status
5. Haematology (including full blood count and blood clotting)
6. Biochemical profile (including renal, liver, bone profile, serum magnesium, human chorionic gonadotropin [hCG], glucose and lactate dehydrogenase)
7. Serum triglycerides and cholesterol
8. Isotopic estimation and calculated GFR
9. Isotope bone scintigram (if clinically relevant)
10. Electrocardiogram
11. Plain film chest x-ray
12. Toxicity and late toxicity*
13. Pregnancy test (females of child bearing potential only)
14. Optional blood samples**

* Assessment of toxicity will be performed during and at the end of each cycle, but the safety assessment period for dose limiting toxicities (DLTs) in the phase I stage of the trial will be until the commencement of cycle two or (if only one cycle is given) 36 days.

** Additional blood samples will be requested for pharmacokinetic, pharmacodynamic and translational studies for patients participating in the optional translational sub-study. Permission will also be sought to retrospectively analyse sections of previous histological specimens. Analyses will be performed as part of a future translational study that will be submitted for separate funding and addressed by separate questions on the patient consent form.

Disease response/progression and performance status will be assessed by cross-sectional imaging at baseline, after cycle three of treatment (week 9) and 6 and 12 months after date of enrolment. If results confirm sufficient activity of the three-drug chemotherapy, the combination treatment will be taken forward into a randomised phase III setting.

Intervention type



Phase I/II

Drug names

Temsirolimus (Torisel®), cisplatin, gemcitabine

Primary outcome measure

Phase I:
1. Safety: dose-limiting toxicities and maximum tolerated dose (MTD)
2. Determination of recommended dose for phase II

Phase II:
Activity: progression-free survival at six months after date of enrolment.

Secondary outcome measures

Phase II:
1. Tolerability and feasibility of use: determined as the number of patients requiring dose delays or reduction and/or treatment withdrawal and will be determined at the end of phase I if the trial does not progress to phase I, otherwise after all patients have completed phase II treatment
2. Objective response rate: determined relative to baseline prior to treatment cycle four (week nine) and at 6 and 12 months from date of completion of treatment
3. Progression-free-survival, time-to-event: calculated as the time from enrolment to any disease progression and/or death patients after all patients have completed at least six months follow-up. Where there is no evidence of progression, patients will be censored at the date last seen.
4. Overall survival: calculated at the end of the study duration (2.5 years) based on the time of enrolment to date of death or date censored (date last known to be alive)
5. Toxicity, during and after treatment: measured at baseline (less than or equal to one week before treatment) and every 21 days whilst on treatment to coincide with the beginning of each new treatment cycle. Late toxicity will be measured at the end of treatment, and at 6 and 12 months from date of enrolment. Serious adverse events (SAEs) will be collected in real time.

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

1. Aged greater than or equal to 18 years, either sex
2. Histologically confirmed transitional cell carcinoma (pure or mixed histology) of urothelium (upper or lower urinary tract)
3. Radiologically evaluable locally advanced and/or metastatic disease (T4b Nany Many, Tany N2-3 Many or Tany Nany M1)
4. Not amenable to curative treatment with surgery or radiotherapy. Patients enrolled in the phase II stage of the trial must have radiologically measurable disease
5. Estimated life expectancy greater than three months
6. World Health Organization (WHO) performance status 0 - 2
7. Fit to receive cisplatin-containing combination chemotherapy
8. No prior systemic therapy for locally advanced or metastatic disease - patients who have received prior neoadjuvant or adjuvant chemotherapy for urothelial cancer (up to four cycles), completed at least six months prior to first documented disease progression will remain eligible)
9. No prior radiotherapy within one month prior to registration or involving more than 30% of total bone marrow volume
10. No investigational drug within one month prior to registration
11. Adequate renal function (glomerular filtration rate [GFR] greater than 60 ml/min, uncorrected for surface area and measured by isotopic means)
12. Adequate bone marrow function (absolute neutrophil count greater than or equal to 1.5 x 10^9/l; platelets greater than or equal to 100 x 10^9/l at baseline)
13. Adequate liver function (bilirubin less than or equal to 1.5 x upper limit of normal [ULN]; alanine aminotransferase [ALT] and alkaline phosphatase [ALP] less than or equal to 2.5 ULN at baseline)
14. Prothrombin time (PT) or International normalised ratio (INR) less than or equal to 1.5 x ULN
15. Written informed consent

Participant type


Age group




Target number of participants


Total final enrolment


Participant exclusion criteria

1. Considered with a view to possible cure
2. Previous malignancy other than non-melanoma skin cancer, cervical carcinoma in situ or incidental localised prostate cancer
3. Previously-identified central nervous system (CNS) metastases - routine baseline computed tomography (CT) scanning of the head is not a requirement for trial entry and should only be performed if clinically indicated
4. Women who are pregnant or breast feeding. Woman of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of trial therapy.
5. Men and women not prepared to practice method(s) of birth control of established efficacy
6. Known infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C
7. Uncontrolled hypertension
8. Symptomatic coronary artery disease, myocardial infarction within the last six months, congestive cardiac failure greater than New York Heart Association (NYHA) class II, uncontrolled or symptomatic cardiac arrhythmia
9. Clinically significant bacterial or fungal infection
10. Concurrent anticoagulant therapy with warfarin or un-fractionated heparin - patients requiring anti-coagulation may be entered after successful conversion to low molecular weight heparin (LMWH)
11. Concomitant medication which have adverse interactions with temsirolimus

Recruitment start date


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

St. James's University Hospital
United Kingdom

Sponsor information


Cardiff University (UK)

Sponsor details

Research and Commercial Division (RACD)
7th Floor
30 - 36 Newport Road
United Kingdom

Sponsor type




Funder type


Funder name

Cancer Research UK (CRUK) (UK) (ref: C7838/A9346) - grant funded by the Feasibility Study Committee (FSC)

Alternative name(s)


Funding Body Type

private sector organisation

Funding Body Subtype

Other non-profit organizations


United Kingdom

Funder name

Wyeth Pharmaceuticals (UK) - provided temsirolimus and its distribution costs free-of-charge (subject to contract)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

The Wales Cancer Trials Unit (WCTU) is core funded by CRUK and WCTU core resources will be used to support this trial.

Alternative name(s)

Funding Body Type

Funding Body Subtype


Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)

See (added 20/05/2019)

Publication list

2017 abstract in:

Publication citations

Additional files

Editorial Notes

20/05/2019: The following changes were made to the trial record: 1. Added link to basic results (scientific). 2. The total final enrollment was added. 05/03/2019: No publications found, verifying study status with principal investigator. 27/06/2016: No publications found, verifying study status with principal investigator.