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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
OBJECTIVES: Primary 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. Secondary 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 progression or unacceptable toxicity. Arm II: Patients receive oral placebo once daily in the absence of disease progression or unacceptable toxicity. 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.

Official Title
-----------------
A Phase II/III, Randomised, Two-Arm, Comparison of Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With HER1 and/or HER2 Overexpressing Locally Advanced or Metastatic Bladder Cancer [LaMB]

Conditions
-----------------
Bladder Cancer

Intervention / Treatment
-----------------
* Drug: lapatinib ditosylate
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral lapatinib ditosylate once daily in the absence of disease progression or unacceptable toxicity. | Drug: lapatinib ditosylate<br>* Given orally<br>* Other names: Tyverb;|
| Placebo Comparator: Arm II<br>Patients receive oral placebo once daily in the absence of disease progression or unacceptable toxicity. | Other: Placebo<br>* Given orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | Disease Progression - at least 20% increase in the sum of longest diameters of target lesions. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IV bladder cancer, transitional cell carcinoma of the bladder