Clinical trial NCT00949455: A Double Blind Randomised Study of Lapatinib and Placebo in Metastatic TCC of the Urothelium
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]
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Bladder Cancer
Keywords: stage IV bladder cancer
transitional cell carcinoma of the bladder
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2009-07-30
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Progression free survival
timeFrame: Disease Progression - at least 20% increase in the sum of longest diameters of target lesions.
Secondary outcomes:
measure: Overall survival
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Barts and the London NHS Trust
state: England
city: Aberdeen
country: United Kingdom
facility: NHS Grampian - Aberdeen Royal Infirmary
city: Basildon
country: United Kingdom
facility: Basildon and Thurrock University Hospital NHS Trust - Basildon Hospital
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust - Birmingham University Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth and Christchurch NHS Foundation Trust - Royal Bournemouth Hospital
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Trust - Bristol University Hospital
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Trust - Addenbrooke's Hospital
city: Chelmsford
country: United Kingdom
facility: Mid Essex NHS Trust - Broomfield Hospital
city: Colchester
country: United Kingdom
facility: Colchester University Hospitals NHS Trust
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry & Warwickshire NHS Trust
city: Derby
country: United Kingdom
facility: Derby Hospitals NHS Trust - Royal Derby Hospital
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde - The Beatson
city: Huddersfield
country: United Kingdom
facility: Calderdale and Huddersfield NHS Trust - Huddersfield Royal Infirmary
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: Liverpool
country: United Kingdom
facility: Clatterbridge Centre for Oncology NHS Trust
city: London
country: United Kingdom
facility: Guys & St Thomas' Hospital NHS Trust - Guys Hospital
city: London
country: United Kingdom
facility: Imperial Healthcare NHS Trust
city: London
country: United Kingdom
facility: Royal Marsden NHS Trust
city: Middlesborough
country: United Kingdom
facility: South Tees NHS Trust - James Cook University Hospital
city: Newcastle
country: United Kingdom
facility: Newcastle Upon Tyne Hospitals NHS Trust
city: Northampton
country: United Kingdom
facility: Northampton General Hospitals NHS Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Nottingham
country: United Kingdom
facility: Sherwood Forest Hospitals NHS Trust - Kings Mill Hospital
city: Portsmouth
country: United Kingdom
facility: Portsmouth Hospitals NHS Trust - Queen Alexandra Hospital
city: Romford
country: United Kingdom
facility: Barking, Havering and Redbridge NHS Trust - Queens Hospital
city: Taunton
country: United Kingdom
facility: Taunton and Somerset NHS Trust - Musgrove Park Hospital
Study officials:
affiliation: Queen Mary University of London
name: Thomas Powles, MD, MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bellmunt J, Werner L, Bamias A, Fay AP, Park RS, Riester M, Selvarajah S, Barletta JA, Berman DM, de Muga S, Salido M, Gallardo E, Rojo F, Guancial EA, Bambury R, Mullane SA, Choueiri TK, Loda M, Stack E, Rosenberg J. HER2 as a target in invasive urothelial carcinoma. Cancer Med. 2015 Jun;4(6):844-52. doi: 10.1002/cam4.432. Epub 2015 Feb 26.