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A Randomized Phase II Trial of Carboplatin and Gemcitabine +/- Vandetanib in First Line Treatment of Advanced Urothelial Cell Cancer in Patients Who Are Not Suitable to Receive Cisplatin

Phase 2
18 Years
Open (Enrolling)
Bladder Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Ureter Cancer, Urethral Cancer

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Trial Information

A Randomized Phase II Trial of Carboplatin and Gemcitabine +/- Vandetanib in First Line Treatment of Advanced Urothelial Cell Cancer in Patients Who Are Not Suitable to Receive Cisplatin



- To determine the antitumor activity (as measured by progression-free survival) of
carboplatin and gemcitabine hydrochloride with versus without vandetanib as first-line
treatment in patients with locally advanced or metastatic urothelial cell cancer who
are not suitable to receive cisplatin.


- To determine the safety, feasibility, and tolerability of these regimens in these

- To determine the objective response rate.

- To determine the overall survival of patients treated with these regimens

- To assess the change of size of measurable lesions at 9 weeks of study therapy.

OUTLINE: This is a multicenter study. Patients are stratified according to relevant factors.
Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive carboplatin IV over 30 minutes on day 1, gemcitabine
hydrochloride IV over 30 minutes on days 1 and 8, and an oral placebo once daily on
days 1-21. Treatment repeats every 3 weeks for 6 courses in the absence of disease
progression or unacceptable toxicity.

- Arm II: Patient receive carboplatin and gemcitabine hydrochloride as in arm I. Patients
also receive oral vandetanib once daily on days 1-21. Treatment repeats every 3 weeks
for 6 courses in the absence of disease progression or unacceptable toxicity.

Blood and urine samples may be collected for laboratory analysis at baseline and after
completion of study.

After completion of study treatment, patients are followed up at weeks 18, 26, 39, and 52.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Inclusion Criteria


- Histologically confirmed transitional cell carcinoma (pure or mixed histology) of the
urothelium (upper or lower urinary tract)

- Cancers with other pathologies are permitted provided the dominant morphology is
transitional cell carcinoma

- Radiologically measurable disease according to RECIST v 1.1 criteria

- Locally advanced and/or metastatic disease not amenable to curative treatment with
surgery or radiotherapy

- Patient not suitable for cisplatin therapy, meeting 1 or more of the following

- More than 75 years of age

- ECOG performance status > 2

- Creatinine clearance < 30 mL/min

- Clinically significant ischemic heart disease (myocardial infarction or unstable
angina more than 3 but less than 12 months prior to date of randomization,
symptomatic angina, or NYHA class I within 3 months prior to date of

- Prior intolerance of cisplatin

- Any other factor that, in the opinion of the investigator, indicates that
cisplatin is not suitable for the patient (e.g., unilateral hearing loss)


- See Disease Characteristics

- ECOG performance status 0-2

- Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)

- Creatinine clearance ≥ 30 mL/min

- Potassium ≥ 4.0 mmol/L OR below the CTCAE grade 1 upper limit

- Magnesium normal OR below the CTCAE grade 1 upper limit

- Serum calcium ≤ 2.9 mmol/L (If serum calcium is < lower limit of normal [LLN], then
adjusted serum calcium must be ≥ LLN)

- ALT/AST ≤ 2.5 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN (< 5 times ULN if judged by the investigator to
be related to liver metastases)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier-method contraception during and for 3
months (women) or 2 months (men) after completion of study therapy

- No evidence of severe or uncontrolled systemic disease or any concurrent condition
that, in the investigator's opinion, makes it undesirable for the patient to
participate in the trial or that would jeopardize compliance with the protocol

- No significant risk of cardiac complications, defined as any of the following:

- Clinically significant cardiovascular event (e.g., myocardial infarction,
superior vena cava syndrome [SVC], NYHA classification of heart disease ≥ class
II within 3 months prior to entry, or presence of cardiac disease that, in the
opinion of the investigator, significantly increases the risk of ventricular

- History of arrhythmia (multifocal premature ventricular contractions, bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is
symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained
ventricular tachycardia

- Atrial fibrillation, controlled on medication, is not exclusionary

- No QTc prolongation with other medications that requires discontinuation of that

- No congenital long QT syndrome or first-degree relative with unexplained sudden death
under 40 years of age

- No QTc that is immeasurable or ≥ 480 msec on screening ECG

- If a patient has a QTc interval ≥ 480 msec on screening ECG, the ECG screen may
be repeated twice (at least 24 hours apart) and the average QTc from the three
screening ECGs must be < 480 msec in order for the patient to be eligible for
the study

- Patients who are receiving a drug that has a risk of Torsades de Pointes are
excluded if QTc is ≥ 460 msec

- No presence of left bundle branch block

- No hypertension not controlled by medical therapy (systolic blood pressure > 160 mm
Hg or diastolic blood pressure > 100 mm Hg)

- No currently active diarrhea that, in the investigator's opinion, may affect the
ability of the patient to either absorb vandetanib or to tolerate additional diarrhea

- No previous or current malignancies of other histology within the past 5 years except
for carcinoma in situ of the cervix, adequately treated basal cell or squamous cell
carcinoma of the skin, or prostate cancer


- See Disease Characteristics

- At least 2 weeks since prior and no concurrent known potent CYP3A4 inducers (e.g.,
barbiturates, rifampicin, rifabutin, phenytoin, carbamazepine, troglitazone,
phenobarbital, or St. John wort) or medication that has known adverse interactions
with vandetanib

- Dexamethasone (or equivalent) allowed as a pre-medication for chemotherapy

- At least 4 weeks since prior major surgery and complete surgical wound healing

- At least 30 days since prior and no other concurrent investigational agents

- No prior chemotherapy (unless delivered perioperatively and completed > 12 months
prior to first presentation of recurrent disease)

- No other concurrent anticancer drug

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Progression Free Survival

Outcome Description:

Time to event PFS, follow-up to 1 year

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Robert Jones, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Glasgow


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

June 2010

Completion Date:

December 2014

Related Keywords:

  • Bladder Cancer
  • Transitional Cell Cancer of the Renal Pelvis and Ureter
  • Ureter Cancer
  • Urethral Cancer
  • metastatic transitional cell cancer of the renal pelvis and ureter
  • regional transitional cell cancer of the renal pelvis and ureter
  • transitional cell carcinoma of the bladder
  • stage III bladder cancer
  • stage IV bladder cancer
  • anterior urethral cancer
  • posterior urethral cancer
  • urethral cancer associated with invasive bladder cancer
  • ureter cancer
  • Urinary Bladder Neoplasms
  • Ureteral Neoplasms
  • Urethral Neoplasms
  • Carcinoma, Transitional Cell
  • Kidney Neoplasms
  • Urologic Neoplasms