A Double Blind Randomised Study of Lapatinib and Placebo in Metastatic TCC of the Urothelium

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:
• 2+ or 3+ intensity on IHC
• Able to commence the study treatment within 10 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)
• 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 non life-threatening tumours that have been curatively treated.
• 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 10 weeks since first-line chemotherapy
• 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