Iressa and Taxotere Study in Patients With Metastatic Urothelial Cancer
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms
Intervention: Docetaxel; ZD1839; Dexamethasone
Intervention description: 25 mg/m2 IV over 30 minutes for 4 weeks, followed by 2 weeks off therapy.; 250 mg by mouth daily, without break.; Course #1: 3 doses of prophylactic Dexamethasone 4mg orally every 12 hours, starting the night before the Docetaxel infusion.
Course #2: If no hypersensitivity reactions and no significant fluid retention during course 1, the Dexamethasone is reduced to 4mg orally twice daily on the day of therapy.
Course #3 and subsequent courses: If no hypersensitivity reactions and no significant fluid retention during course 2, the Dexamethasone is reduced to 4mg orally one hour before treatment.
Intervention MeSH terms: Dexamethasone; Docetaxel; Gefitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Healthy volunteers: No
Keywords: Transitional Cell Carcinoma; Urothelium; Urothelial Cancer; Bladder Cancer; Docetaxel; Taxotere; ZD1839; Gefitinib; Iressa; Consolidation Therapy

Summary:

      Primary Objective:

      1. To compare the proportion of patients free from progression 9 months from the start of
      consolidation therapy with the combination of docetaxel and ZD1839 (Iressa) versus docetaxel
      alone. For the purposes of this protocol, "consolidation" therapy refers to treatment given
      at the time of maximal benefit from conventional front-line multi-agent chemotherapy.

      Secondary Objective:

      1. To compare time to progression (TTP), overall survival (OS) and cause-specific survival
      (CSS) in the two arms. For completeness, these will be reported both from the initiation of
      consolidation chemotherapy, and from the completion of induction chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  All patients must have histologic demonstration of metastatic or locally unresectable
             transitional cell carcinoma of the urothelium. Minor components (<50% overall) of
             variants such as glandular or squamous differentiation, or evolution to more
             aggressive phenotypes such as sarcomatoid of small cell change are acceptable.
             However, when these atypical histologies are dominant, other treatment approaches may
             be appropriate, and such patients are not eligible.

          -  All patients must have demonstrated some objective response to combination
             chemotherapy, and be clinically without progression since this response was
             appreciated. In general, patients will have been treated with at least two successive
             combination regimens in order to achieve maximum benefit from available chemotherapy.

          -  Patients who have not achieved a complete response to therapy must have received one
             of the chemotherapy regimens outlined in Appendix D prior to receiving consolidation
             therapy. Exceptions to this generalization would include patients with a near complete
             response to the first regimen given, or patients that are not fit for aggressive
             chemotherapy beyond an initially used regimen to which they responded. Patients must
             begin "consolidation" therapy within 6 weeks of the end of the last cycle of induction
             chemotherapy, and should begin as soon as possible.

          -  Zubrod performance status of 3 or better. If PS = 3 this must, in the opinion of the
             investigator, be secondary to the effects of induction chemotherapy and not the
             underlying cancer.

          -  Patients with a history of cardiac disease, or an ejection fraction (EF) less than 50%
             at the time of initiation of chemotherapy, must be demonstrated to have an ejection
             fraction of at least 40%. In addition, patients having received more than 250 mg/m^2
             of doxorubicin during their induction phase, or who have EKG changes since initiation
             of chemotherapy must have an EF of at least 45%. Patients with no history of cardiac
             disease, a normal EKG and no more than 250 mg/m^2 of doxorubicin are not required to
             have an EF measurement.

          -  Provision of written informed consent.

          -  Women of childbearing potential must be willing to practice acceptable methods of
             birth control to prevent pregnancy.

          -  Males taking ZD1839 must also use birth control while taking the drug to avoid
             pregnancy in their partner.

          -  International normalized ratio (INR) elevations, bleeding, or both events have been
             reported in some patients taking warfarin. Patients taking warfarin with a target INR
             of > or = 2, should be monitored regularly (every week in the first cycle, with
             further monitoring based on the experience in the first cycle) for changes in
             prothrombin time (PT) or INR. Patients on prophylactic low dose warfarin (ie: 1-2 mg
             qd for central line thrombosis prophylaxis) do not require frequent monitoring.

        Exclusion Criteria:

          -  Predominantly small cell histology.

          -  AST or conjugated bilirubin greater than twice the upper limit of normal.

          -  Serum creatinine greater than 2.5 mg/dL , or a creatinine clearance (either measured
             or estimated by Cockcroft formula) of less than 25 mL/min: creatinine clearance (CLcr)
             = [(140-age) x wt(kg)]/[72 xCreat (mg/dL)] (Multiply by 0.85 for females)

          -  Absolute neutrophil count (ANC) less than 1,000; Platelets less than 75,000.

          -  Prior (lifetime) cumulative exposure to doxorubicin greater than 400 mg/m^2.

          -  Pregnant and lactating women are excluded. Women of childbearing potential must have a
             negative pregnancy test prior to starting therapy.

          -  An active, or likely to become active, second malignancy.

          -  Known severe hypersensitivity to ZD1839 or any of the excipients of this product.

          -  Concomitant use of phenytoin, carbamazepine, barbiturates, rifampin, phenobarbital of
             St. John's Wort

          -  Treatment with a non-approved or investigational drug within 30 days before Day 1 of
             trial treatment.

          -  Incomplete healing from previous oncologic or other major surgery

          -  Note that there is no requirement for measurable or evaluable disease. Evaluation of
             response to therapy is not an endpoint of this trial.

          -  Prior treatment with therapy which specifically targets the HER family of receptors.

          -  Patients with peripheral neuropathy > or = to grade 2 should be excluded. Patients may
             be included if their neuropathy has resolved to grade 1 by the time they are
             registered on the protocol.

          -  Evidence of any other significant clinical disorder or laboratory finding that makes
             it undesirable for the subject to participate in the trial.

          -  As judged by the investigator, any evidence of severe or uncontrolled systemic disease
             (e.g., unstable or uncompensated respiratory, cardiac, hepatic or renal disease).

          -  Any evidence of clinically active interstitial lung disease (patients with chronic
             stable radiographic changes who are asymptomatic need not be excluded).