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

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