Clinical trial NCT00820222: Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in ErbB2 (HER2) Positive Metastatic Breast Cancer
Official title: A Randomized, Multicentre, Open-Label, Phase III Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Anthracycline- or Taxane-Exposed ErbB2-Positive Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastases, Brain
Keywords: ErbB2
HERCEPTIN
XELODA
ErbB1
TYKERB
metastatic breast cancer
trastuzumab
breast cancer
capecitabine
lapatinib
brain metastases
HER2 positive
TYVERB
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-01-12
Enrollment: 540
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This open label study was designed to evaluate Lapatinib effect on incidence of brain metastases in ErbB2 (HER2) positive metastatic breast cancer patients exposed to prior taxanes or anthracyclines.

Detailed description: The study was terminated based on the IDMC recommendation in 2012, collection of efficacy outcome measures was discontinued and all primary and secondary outcome measures were reported in 2012.

An amendment protocol allowed subjects who were on study treatment to enroll in a Long Term Follow Up (LTFU) phase if they had evidence of clinical benefit but no local access to standard of care treatments. Subjects received study treatment until disease progression, unacceptable toxicity, or subject withdrawal. In LTFU only Adverse Events data were collected. For the LTFU the Outcome Measure "Number of participants with the indicated Grade 3 or Grade 4 Adverse Events (AEs) occurring in \>=2% of participants in either treatment arm" and "Adverse Events" were updated.

Eligibility criteria: Inclusion Criteria:

* Females at least 18 years old;
* ECOG Performance Status 0-2;
* Histologically or cytologically confirmed HER2-positive invasive breast cancer, with Stage IV disease;
* Prior treatment with taxanes or anthracyclines is required;
* Prior treatment with other chemotherapeutic agents, trastuzumab, endocrine and radiation therapy is permitted;
* Baseline LVEF ≥ 50% and not lower than the institutional lower limit of normal;
* Concurrent treatment with bisphosphonates is permitted, however treatment must be initiated prior to the first dose of study therapy;
* Able to swallow and retain oral medications;
* Women with potential to have children must be willing to practice acceptable methods of birth control during the study;
* Normal organ and marrow function.

Exclusion Criteria:

* History and/or current evidence of CNS metastases. Baseline MRI scan by Independent Reviewer to confirm no brain mets;
* Concurrent treatment with an investigational agent or participation in another treatment clinical trial;
* Prior therapy with lapatinib or an ErbB2 inhibitor other than trastuzumab (including but not limited to trastuzumab-DM1 and neratinib) and capecitabine;
* Known DPD deficiency;
* Concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy, or hormonal therapy for treatment of cancer;
* History of allergic reactions attributed to compounds chemically related to lapatinib (quinazolines), capecitabine, fluorouracil or any excipients;
* Concomitant use of CYP3A4 inhibitors or inducers;
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel;
* History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents, or other contraindication to gadolinium contrast and other known contraindication to MRI;
* Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the patient's safety or compliance to study procedures;
* have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease);
* Any on-going toxicity from prior anti cancer therapy except alopecia;
* Active cardiac disease;
* Uncontrolled infection;
* History of other malignancy, unless curatively treated with no evidence of disease for at least 5 years, subjects with adequately treated DCIS or LCIS, adequately treated non-melanoma skin cancer or curatively treated in-situ cancer of the cervix are eligible;
* Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of protocol treatment;
* Pregnant or lactating females.

Primary outcomes:
measure: Number of Participants With Central Nervous System (CNS) Metastases (as Assessed by Independent Review) as the Site of First Relapse
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
Secondary outcomes:
measure: Progression Free Survival (PFS), as Assessed by the Investigator
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
measure: Time to First CNS Progression, Defined as the Time From Randomization Until the Date of Documented CNS Progression as the First Site of Relapse
timeFrame: From randomization until the date of documented CNS progression (average of 10 months). Cut-off 11-Jun-2012
measure: Overall Survival
timeFrame: From randomization until death due to any cause (average of 10 months). Cut-off 11-Jun-2012
measure: Number of Participants With Overall Response (OR), as Assessed by the Investigator
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
measure: Number of Participants With Clinical Benefit (CB)
timeFrame: From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
measure: Duration of Response
timeFrame: From the time of the first documented confirmed complete or partial response until disease progression or death, if sooner (average of 10 months). Cut-off 11-Jun-2012
measure: Number of Participants With CNS Progression at Any Time
timeFrame: From the time of randomization until death due to any cause (average of 10 months). Cut-off 11-Jun-2012
measure: Number of Participants With Qualitative and Quantitative Toxicities
timeFrame: From the first dose of study medication until 30 days after the last dose of study treatment (average of 10 months)
measure: Number of Participants Expressing Glucocorticoid Receptor, Phosphatase and Tensin Homolog (PTEN), Phosphatidylinositide 3-kinase (PI3K)/AKT, Protein 53 (P53), Insulin-like Growth Factor-1 (IGF-1), and Genes Involved in Cell Cycle Regulation
timeFrame: Baseline
measure: Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events (AEs) Occurring in >=2% of Participants in Either Treatment Arm
timeFrame: From the first dose of study medication until 30 days after the last dose of study treatment (average of 10 months).
Other outcomes:
Locations:
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facility: Novartis Investigative Site
state: Arizona
city: Tucson
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facility: Novartis Investigative Site
state: Arizona
city: Jonesboro
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Anaheim
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facility: Novartis Investigative Site
state: California
city: Greenbrae
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facility: Novartis Investigative Site
state: California
city: Sacramento
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facility: Novartis Investigative Site
state: California
city: Santa Barbara
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facility: Novartis Investigative Site
state: California
city: Washington
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facility: Novartis Investigative Site
state: District of Columbia
city: Boca Raton
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facility: Novartis Investigative Site
state: Florida
city: Coral Springs
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facility: Novartis Investigative Site
state: Florida
city: Hollywood
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facility: Novartis Investigative Site
state: Florida
city: Warrenville
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facility: Novartis Investigative Site
state: Illinois
city: Metairie
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facility: Novartis Investigative Site
state: Louisiana
city: Saint Louis
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facility: Novartis Investigative Site
state: Missouri
city: Great Falls
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facility: Novartis Investigative Site
state: Montana
city: Voorhees
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facility: Novartis Investigative Site
state: New Jersey
city: Durham
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Antwerpen
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Sint-Niklaas
country: Belgium
facility: Novartis Investigative Site
city: Aarhus
country: Denmark
facility: Novartis Investigative Site
city: Angers cedex 9
country: France
facility: Novartis Investigative Site
city: Avignon
country: France
facility: Novartis Investigative Site
city: Bayonne cedex
country: France
facility: Novartis Investigative Site
city: Besancon
country: France
facility: Novartis Investigative Site
city: Caen Cedex 05
country: France
facility: Novartis Investigative Site
city: Colmar
country: France
facility: Novartis Investigative Site
city: Dechy
country: France
facility: Novartis Investigative Site
city: Nancy
country: France
facility: Novartis Investigative Site
city: Paris cedex 13
country: France
facility: Novartis Investigative Site
city: Reims Cedex
country: France
facility: Novartis Investigative Site
city: Reims
country: France
facility: Novartis Investigative Site
city: Saint Priest En Jarez Cedex
country: France
facility: Novartis Investigative Site
city: Saint-Gregoire
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Vannes
country: France
facility: Novartis Investigative Site
city: Ravensburg
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Eggenfelden
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Fuerth
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Landshut
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Nuernberg
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Rosenheim
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Potsdam
country: Germany
facility: Novartis Investigative Site
state: Brandenburg
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Wiesbaden
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Bottrop
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Duisburg
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Goch
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Herne
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Velbert
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Witten
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Wuerselen
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: Novartis Investigative Site
state: Rheinland-Pfalz
city: Speyer
country: Germany
facility: Novartis Investigative Site
state: Rheinland-Pfalz
city: Halle
country: Germany
facility: Novartis Investigative Site
state: Sachsen-Anhalt
city: Luebeck
country: Germany
facility: Novartis Investigative Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Brandenburg
country: Germany
facility: Novartis Investigative Site
city: Bremen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: N. Kifisia, Athens
country: Greece
facility: Novartis Investigative Site
city: Neo Faliro
country: Greece
facility: Novartis Investigative Site
city: Patra
country: Greece
facility: Novartis Investigative Site
city: Peiraius
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Kaposvar
country: Hungary
facility: Novartis Investigative Site
city: Tatabanya
country: Hungary
facility: Novartis Investigative Site
city: Veszprem
country: Hungary
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: Emilia-Romagna
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: Emilia-Romagna
city: Meldola (FC)
country: Italy
facility: Novartis Investigative Site
state: Emilia-Romagna
city: Rimini
country: Italy
facility: Novartis Investigative Site
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state: Lazio
city: Monza
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facility: Novartis Investigative Site
state: Lombardia
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
state: Trentino-Alto Adige
city: Perugia
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facility: Novartis Investigative Site
state: Umbria
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country: Italy
facility: Novartis Investigative Site
city: Bydgoszcz
country: Poland
facility: Novartis Investigative Site
city: Bytom
country: Poland
facility: Novartis Investigative Site
city: Gliwice
country: Poland
facility: Novartis Investigative Site
city: Konin
country: Poland
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city: Lodz
country: Poland
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city: Olsztyn
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country: Poland
facility: Novartis Investigative Site
city: Wroclaw
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city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Arkhangelsk
country: Russian Federation
facility: Novartis Investigative Site
city: Chelyabinsk
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facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Kirov
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow Region
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Obninsk
country: Russian Federation
facility: Novartis Investigative Site
city: Petrozavodsk
country: Russian Federation
facility: Novartis Investigative Site
city: Ryazan
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Tver
country: Russian Federation
facility: Novartis Investigative Site
city: Velikiy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Voronezh
country: Russian Federation
facility: Novartis Investigative Site
city: Vsevolozhsk
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Caceres
country: Spain
facility: Novartis Investigative Site
city: Hospitalet de Llobregat (Barcelona)
country: Spain
facility: Novartis Investigative Site
city: Jerez (Cadiz)
country: Spain
facility: Novartis Investigative Site
city: La Coruna
country: Spain
facility: Novartis Investigative Site
city: Lerida
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
city: Palma de Mallorca
country: Spain
facility: Novartis Investigative Site
city: Palma de Mallorca
country: Spain
facility: Novartis Investigative Site
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
city: Torrevieja (Alicante)
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Vasteras
country: Sweden
facility: Novartis Investigative Site
city: Vaxjo
country: Sweden
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiangmai
country: Thailand
facility: Novartis Investigative Site
city: Songkla
country: Thailand
facility: Novartis Investigative Site
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
state: Midlothian
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
state: West Midlands
city: Aberdeen
country: United Kingdom
facility: Novartis Investigative Site
city: Burton on Trent
country: United Kingdom
facility: Novartis Investigative Site
city: Cottingham, Hull
country: United Kingdom
facility: Novartis Investigative Site
city: Huddersfield
country: United Kingdom
facility: Novartis Investigative Site
city: Ipswich
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Maidstone
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
city: Peterborough
country: United Kingdom
facility: Novartis Investigative Site
city: Sheffield
country: United Kingdom
facility: Novartis Investigative Site
city: Shrewsbury
country: United Kingdom
facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
city: Wolverhampton
country: United Kingdom
facility: Novartis Investigative Site
city: Worthing
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Pivot X, Manikhas A, Zurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. doi: 10.1200/JCO.2014.57.1794. Epub 2015 Jan 20.