RATIONALE: Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the
enzymes needed for cell growth. It is not yet known whether lapatinib ditosylate is more
effective than a placebo in killing tumor cells.
PURPOSE: This randomized phase II/III trial is studying how well lapatinib ditosylate works
compared to a placebo in treating patients with stage IV bladder cancer.
- Compare progression-free survival in patients with HER1- and/or HER2-overexpressing
stage IV bladder cancer who have been randomized to maintenance therapy with lapatinib
ditosylate or placebo following first-line chemotherapy.
- Compare overall survival between these patient groups.
- Evaluate the safety and tolerability of the regimens in these patients.
- Assess and compare quality of life between these patient groups.
OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance
status and response to first line chemotherapy (complete or partial response vs stable
disease). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive oral lapatinib ditosylate once daily in the absence of disease
- Arm II: Patients receive oral placebo once daily in the absence of disease progression
Patients undergo quality of life assessment by EORTC QLQ-C30 at baseline and every 4 weeks
during study treatment.
After completion of study treatment, patients are followed up periodically for up to 5
years.
DISEASE CHARACTERISTICS:
- Histologically confirmed transitional cell carcinoma of the bladder
- Stage IV disease
- Metastatic or locally advanced disease
- HER1- and/or HER2-positive disease, defined by the following criteria:
- Gene amplification on FISH
- 2+ or 3+ intensity on IHC
- Able to commence the study treatment within 8 weeks of completing chemotherapy
- Must have achieved objective response or stable disease following 4-8 courses of
first-line chemotherapy
- No progression with first-line chemotherapy for metastatic disease
- Any widely accepted chemotherapy regimen for bladder cancer allowed
- Patients who did not receive cisplatin are eligible
PATIENT CHARACTERISTICS:
- ECOG performance status 0-3
- ANC ≥ 1. 0 x 10^9/L
- Hemoglobin ≥ 8. 0 g/dL
- Platelet count ≥ 75 x 10^9/L
- ALT/AST < 2 times upper limit of normal (ULN)
- Alkaline phosphatase < 2 times ULN
- Bilirubin < 1. 5 times ULN
- Serum creatinine ≤ 3. 0 ULN AND/OR creatinine clearance ≥ 30 mL/min
- LVEF ≥ 50% (as assessed by quantitative echocardiogram or MUGA)
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No current active hepatic or biliary disease, except for any of the following:
- Gilbert's syndrome
- Asymptomatic gallstones
- Liver metastases
- Stable chronic liver disease per investigator assessment
- No known hypersensitivity to the study medication
- No history of prior or concurrent other neoplasms, except for any of the following:
- Curatively treated nonmelanoma skin cancer
- Adequately treated in situ carcinoma of the cervix
- Other cancer curatively treated with no evidence of disease for ≥ 5 years
- Prostate cancer isolated to the prostate gland
- No significant cardiac disease, including any of the following:
- Angina pectoris
- Severe cardiac arrhythmia requiring medication
- Severe conduction abnormalities
- Clinically significant valvular disease
- Cardiomegaly
- Prior myocardial infarction
- Ventricular hypertrophy
- Congestive heart failure
- Poorly uncontrolled hypertension (resting diastolic blood pressure > 115 mm Hg)
- Other cardiomyopathy
- No serious intercurrent medical or psychiatric illness
- No serious active infection
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- No more than 1 line of prior chemotherapy for metastatic or locally advanced disease
(neoadjuvant/adjuvant chemotherapy allowed)
- No more than 8 weeks since first-line chemotherapy
- No prior anti-HER1 or anti-HER2 therapy
- No prior lapatinib ditosylate
- No prior radiotherapy to the indicator lesion(s) (newly arising lesions in previously
irradiated areas allowed)
- At least 14 days since prior and no concurrent CYP3A4 inducers, including but not
limited to, any of the following:
- Antibiotics (all rifamycin class agents [e. g., rifampicin, rifabutin,
rifapentine])
- Anticonvulsants (phenytoin, carbamazepine, barbiturates [e. g., phenobarbital])
- Oral glucocorticoids (cortisone [> 50 mg], hydrocortisone [> 40 mg], prednisone
[> 10 mg], methylprednisolone [> 8 mg], dexamethasone [> 2 mg²])
- St. John's wort or modafinil
- At least 7 days since prior and no concurrent CYP3A4 inhibitors, including but not
limited to, any of the following:
- Antibiotics (clarithromycin, erythromycin, troleandomycin)
- Antifungals (itraconazole, ketoconazole, fluconazole [>150 mg daily],
voriconazole)
- Antiretrovirals/protease inhibitors (delavirdine, nelfinavir, amprenavir,
ritonavir, indinavir, saquinavir, lopinavir)
- Calcium channel blockers (verapamil, diltiazem)
- Antidepressants (nefazodone, fluvoxamine)
- Gastrointestinal agents (cimetidine, aprepitant)
- Grapefruit, grapefruit juice
- At least 6 months since prior and no concurrent amiodarone
- No concurrent radical or curative therapy (radiotherapy or surgery) at the end of
first-line treatment (palliative radiotherapy allowed)
- No other concurrent experimental or investigational drugs
- No other concurrent anticancer treatment, including cytotoxic or specific immune
therapy
