• Progression-free survival [ Designated as safety issue: No ]
  

• Overall survival [ Designated as safety issue: No ]
  
• Objective response rate [ Designated as safety issue: No ]
  
• Incidence of grade 3, grade 4, and serious adverse events [ Designated as safety issue: Yes ]
  

OBJECTIVES:

Primary

• Compare the efficacy of vandetanib in combination with docetaxel vs docetaxel in combination with a placebo in prolonging progression-free survival in patients with previously treated stage IV transitional cell carcinoma.

Secondary

• Compare the efficacy of vandetanib in combination with docetaxel vs docetaxel in combination with a placebo, in terms of improved objective response rates and survival.
• Compare the tolerability and safety of vandetanib in combination with docetaxel vs docetaxel in combination with a placebo by assessing the incidence and nature of grade 3, grade 4, and serious adverse events.
• Compare the efficacy of vandetanib alone, in terms of objective response rates, in patients who cross over onto the vandetanib alone arm after progression.
• Discover biomarkers in the serum or plasma of patients that may predict response to therapy.

OUTLINE: Patients are stratified according to the presence of measurable disease (yes vs no), presence of ECOG performance status of 0 AND no visceral metastasis (yes vs no), and the number of prior systemic chemotherapy regimens, including adjuvant or neoadjuvant regimens (1 vs > 1). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive docetaxel IV over 1 hour on day 1 and oral vandetanib once daily on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive docetaxel IV over 1 hour on day 1 and oral placebo once daily on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Patients in arm II who experience disease progression may cross over to receive open-label vandetanib alone in the absence of unacceptable toxicity or further disease progression.

Patients undergo blood sample collection periodically for biological studies. Samples are analyzed for potential biomarkers associated with angiogenesis (VEGF) and metastatic transitional cell carcinoma.

After completion of study treatment, patients are followed periodically.

DISEASE CHARACTERISTICS:

• Histologically confirmed stage IV transitional cell carcinoma (TCC)

  • Mixed histologies allowed provided the predominant histology is TCC

• Must have received prior chemotherapy* for TCC AND meets at least 1 of the following criteria:

  • Disease progression after treatment with a regimen that included a platinum salt (e.g., carboplatin or cisplatin) for stage IV disease
  • Disease recurrence within 2 years after neoadjuvant or adjuvant treatment with a regimen that included a platinum salt NOTE: *Received 1-3 prior systemic chemotherapy or investigational treatment regimens for TCC

• Measurable or evaluable disease

  • If all sites of measurable or evaluable disease have been irradiated, one site must have demonstrated growth after irradiation

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-1
• ANC ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Serum bilirubin normal
• Creatinine clearance ≥ 30 mL/min
• Potassium ≥ 4.0 mmol/L (supplementation allowed)
• Serum calcium (ionized or adjusted for albumin) normal
• Magnesium normal (supplementation allowed)

• Alkaline phosphatase (AP) and AST/ALT must meet 1 of the following criteria:

  • AP normal AND AST or ALT ≤ 5 times upper limit of normal (ULN)
  • AP ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN
  • AP ≤ 5 times ULN AND AST or ALT normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• 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 trial
• No clinically significant cardiac event, including myocardial infarction; New York Heart Association (NYHA) class III or IV heart disease within the past 3 months; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia
• No history of QTc prolongation from other medication that required discontinuation of that medication
• No congenital long QT syndrome or first degree relative with unexplained sudden death under 40 years of age

• No QTc with Bazett's correction that is unmeasurable OR QTc ≥ 480 msec on screening ECG

  • Patients with a QTc ≥ 480 msec on screening ECG may repeat the ECG twice (at least 24 hours apart)

    • The average QTc from all three ECG screenings must be < 480 msec for the patient to be eligible for the study

• No history of arrhythmia, including multifocal premature ventricular contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation that is symptomatic or requires treatment (CTCAE grade 3)

  • Atrial fibrillation that is controlled with medication allowed
• No asymptomatic sustained ventricular tachycardia
• No left bundle branch block
• No hypertension that cannot be controlled by medical therapy
• No active diarrhea
• No peripheral neuropathy ≥ grade 2
• No other malignancy within the past 5 years except in situ carcinoma of the cervix or adequately treated carcinoma of the skin or localized prostate cancer
• No history of severe hypersensitivity reaction to drugs formulated with polysorbate 80

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from prior therapy (CTC ≤ grade 1)

  • Alopecia allowed
• No prior taxane (e.g., docetaxel or paclitaxel) in any setting (i.e., neoadjuvant, adjuvant, or for metastatic disease) for the treatment of TCC

• No prior VEGF-axis active agents, including any of the following:

  • Antibodies to VEGF
  • Antibodies to VEGF receptors
  • VEGF receptor tyrosine kinase inhibitors
• More than 28 days since prior investigational agents, chemotherapy, or radiotherapy
• More than 4 weeks since prior major surgery and recovered
• No blood product donation during and for 3 months after completion of study treatment
• No other concurrent medication that may cause QTc prolongation, induce torsades de pointes, or induce CYP3A4 function
• No other concurrent chemotherapy, radiotherapy, radiopharmaceuticals, or investigational agents