Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in ErbB2 (HER2) Positive Metastatic Breast Cancer

Metastases, Brain Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00820222
• Other study ID #: 111438
• Status: Completed
• Phase: Phase 3
• Start date: April 14, 2009
• Est. completion date: March 22, 2018

Study information

• Verified date: March 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 540
• Est. completion date: March 22, 2018
• Est. primary completion date: June 11, 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastases, Brain
• Neoplasm Metastasis

Intervention

Drug:
• capecitabine
oral medication; daily dose divided into morning and evening dose and taken for 14 days of 21 day cycle
• lapatinib
oral medication; daily dose taken once a day
• trastuzumab
infusion therapy; loading dose of 8mg/kg, followed by 6mg/kg given every 3 weeks

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Antwerpen
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Sint-Niklaas
Denmark	Novartis Investigative Site	Aarhus
France	Novartis Investigative Site	Angers cedex 9
France	Novartis Investigative Site	Avignon
France	Novartis Investigative Site	Bayonne cedex
France	Novartis Investigative Site	Besancon
France	Novartis Investigative Site	Caen Cedex 05
France	Novartis Investigative Site	Colmar
France	Novartis Investigative Site	Dechy
France	Novartis Investigative Site	Nancy
France	Novartis Investigative Site	Paris cedex 13
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Reims Cedex
France	Novartis Investigative Site	Saint Priest En Jarez Cedex
France	Novartis Investigative Site	Saint-Gregoire
France	Novartis Investigative Site	Strasbourg
France	Novartis Investigative Site	Vannes
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bottrop	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Brandenburg
Germany	Novartis Investigative Site	Bremen
Germany	Novartis Investigative Site	Duisburg	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Eggenfelden	Bayern
Germany	Novartis Investigative Site	Frankfurt	Hessen
Germany	Novartis Investigative Site	Fuerth	Bayern
Germany	Novartis Investigative Site	Goch	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Halle	Sachsen-Anhalt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Herne	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Landshut	Bayern
Germany	Novartis Investigative Site	Luebeck	Schleswig-Holstein
Germany	Novartis Investigative Site	Mainz	Rheinland-Pfalz
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Nuernberg	Bayern
Germany	Novartis Investigative Site	Potsdam	Brandenburg
Germany	Novartis Investigative Site	Ravensburg	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Rosenheim	Bayern
Germany	Novartis Investigative Site	Speyer	Rheinland-Pfalz
Germany	Novartis Investigative Site	Velbert	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Wiesbaden	Hessen
Germany	Novartis Investigative Site	Witten	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Wuerselen	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Wuerzburg	Bayern
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	N. Kifisia, Athens
Greece	Novartis Investigative Site	Neo Faliro
Greece	Novartis Investigative Site	Patra
Greece	Novartis Investigative Site	Peiraius
Greece	Novartis Investigative Site	Thessaloniki
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Kaposvar
Hungary	Novartis Investigative Site	Tatabanya
Hungary	Novartis Investigative Site	Veszprem
Italy	Novartis Investigative Site	Bologna	Emilia-Romagna
Italy	Novartis Investigative Site	Bologna	Emilia-Romagna
Italy	Novartis Investigative Site	Fermo (AP)	Marche
Italy	Novartis Investigative Site	Lido Di Camaiore (LU)	Toscana
Italy	Novartis Investigative Site	Meldola (FC)	Emilia-Romagna
Italy	Novartis Investigative Site	Monza	Lombardia
Italy	Novartis Investigative Site	Novara	Piemonte
Italy	Novartis Investigative Site	Perugia	Umbria
Italy	Novartis Investigative Site	Pisa	Toscana
Italy	Novartis Investigative Site	Rimini	Emilia-Romagna
Italy	Novartis Investigative Site	Roma	Lazio
Italy	Novartis Investigative Site	Trento	Trentino-Alto Adige
Italy	Novartis Investigative Site	Treviglio (BG)	Lombardia
Italy	Novartis Investigative Site	Udine	Friuli-Venezia-Giulia
Italy	Novartis Investigative Site	Varese
Poland	Novartis Investigative Site	Bydgoszcz
Poland	Novartis Investigative Site	Bytom
Poland	Novartis Investigative Site	Gliwice
Poland	Novartis Investigative Site	Konin
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Olsztyn
Poland	Novartis Investigative Site	Rzeszow
Poland	Novartis Investigative Site	Wroclaw
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Arkhangelsk
Russian Federation	Novartis Investigative Site	Chelyabinsk
Russian Federation	Novartis Investigative Site	Kazan
Russian Federation	Novartis Investigative Site	Kirov
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow Region
Russian Federation	Novartis Investigative Site	Nizhniy Novgorod
Russian Federation	Novartis Investigative Site	Obninsk
Russian Federation	Novartis Investigative Site	Petrozavodsk
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	Tver
Russian Federation	Novartis Investigative Site	Velikiy Novgorod
Russian Federation	Novartis Investigative Site	Voronezh
Russian Federation	Novartis Investigative Site	Vsevolozhsk
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Caceres
Spain	Novartis Investigative Site	Hospitalet de Llobregat (Barcelona)
Spain	Novartis Investigative Site	Jerez (Cadiz)
Spain	Novartis Investigative Site	La Coruna
Spain	Novartis Investigative Site	Lerida
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga
Spain	Novartis Investigative Site	Palma de Mallorca
Spain	Novartis Investigative Site	Palma de Mallorca
Spain	Novartis Investigative Site	Santiago de Compostela
Spain	Novartis Investigative Site	Sevilla
Spain	Novartis Investigative Site	Sevilla
Spain	Novartis Investigative Site	Torrevieja (Alicante)
Spain	Novartis Investigative Site	Valencia
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Sweden	Novartis Investigative Site	Vasteras
Sweden	Novartis Investigative Site	Vaxjo
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Chiangmai
Thailand	Novartis Investigative Site	Songkla
United Kingdom	Novartis Investigative Site	Aberdeen
United Kingdom	Novartis Investigative Site	Birmingham	West Midlands
United Kingdom	Novartis Investigative Site	Burton on Trent
United Kingdom	Novartis Investigative Site	Cottingham, Hull
United Kingdom	Novartis Investigative Site	Edinburgh	Midlothian
United Kingdom	Novartis Investigative Site	Huddersfield
United Kingdom	Novartis Investigative Site	Ipswich
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Maidstone
United Kingdom	Novartis Investigative Site	Nottingham
United Kingdom	Novartis Investigative Site	Peterborough
United Kingdom	Novartis Investigative Site	Sheffield
United Kingdom	Novartis Investigative Site	Shrewsbury
United Kingdom	Novartis Investigative Site	Southampton
United Kingdom	Novartis Investigative Site	Wolverhampton
United Kingdom	Novartis Investigative Site	Worthing
United States	Novartis Investigative Site	Anaheim	California
United States	Novartis Investigative Site	Boca Raton	Florida
United States	Novartis Investigative Site	Coral Springs	Florida
United States	Novartis Investigative Site	Durham	North Carolina
United States	Novartis Investigative Site	Goodyear	Arizona
United States	Novartis Investigative Site	Great Falls	Montana
United States	Novartis Investigative Site	Greenbrae	California
United States	Novartis Investigative Site	Hollywood	Florida
United States	Novartis Investigative Site	Jonesboro	Arkansas
United States	Novartis Investigative Site	Metairie	Louisiana
United States	Novartis Investigative Site	Sacramento	California
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Santa Barbara	California
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Voorhees	New Jersey
United States	Novartis Investigative Site	Warrenville	Illinois
United States	Novartis Investigative Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Denmark,  France,  Germany,  Greece,  Hungary,  Italy,  Poland,  Russian Federation,  Spain,  Sweden,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Central Nervous System (CNS) Metastases (as Assessed by Independent Review) as the Site of First Relapse	CNS relapse is defined as the appearance of >=1 enhancing lesion measuring >=6 millimeters (mm) on T1Weighted (T1W) Magnetic Resonance Imaging (MRI) without CNS symptoms that were considered to be unequivocal based on all relevant radiological features (e.g., associated T2W signal abnormality); the appearance of any enhancing lesion on T1W MRI with CNS symptoms; unequivocal finding of leptomeningeal disease (defined as the dissemination of cancer throughout the spinal fluid), with or without symptoms; and unequivocal finding of multifocal intraparenchymal lesions with or without symptoms. In the event of the appearance of a <6 mm lesions(s) without CNS lesions, or equivocal findings potentially suggesting leptomeningeal disease, these findings were followed with a subsequent scan within 6 weeks. If unequivocal progression was determined with the subsequent scan and/or CNS symptoms occurred, then CNS relapse crieria were met.	From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
Secondary	Progression Free Survival (PFS), as Assessed by the Investigator	PFS is defined as the interval between the date of randomization and the earliest date of progressive disease (PD), or death due to any cause. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, compared with the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions based on investigator assessment of both CNS and non-CNS for response.	From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
Secondary	Time to First CNS Progression, Defined as the Time From Randomization Until the Date of Documented CNS Progression as the First Site of Relapse	CNS relapse is defined as the appearance of >=1 enhancing lesion measuring >=6 mm on T1W MRI without CNS symptoms that were considered to be unequivocal based on all relevant radiological features (e.g., associated T2W signal abnormality); the appearance of any enhancing lesion on T1W MRI with CNS symptoms; unequivocal finding of leptomeningeal disease (defined as the dissemination of cancer throughout the spinal fluid), with or without symptoms; and unequivocal finding of multifocal intraparenchymal lesions with or without symptoms. In the event of the appearance of a <6 mm lesions(s) without CNS lesions, or equivocal findings potentially suggesting leptomeningeal disease, these findings were followed with a subsequent scan within 6 weeks. If unequivocal progression was determined with the subsequent scan and/or CNS symptoms occurred, then CNS relapse crieria were met.	From randomization until the date of documented CNS progression (average of 10 months). Cut-off 11-Jun-2012
Secondary	Overall Survival	Overall survival is defined as the time from randomization until death due to any cause or to the date of censor. In the absence of confirmation of death, survival time was to be censored at the time of the last investigator contact.	From randomization until death due to any cause (average of 10 months). Cut-off 11-Jun-2012
Secondary	Number of Participants With Overall Response (OR), as Assessed by the Investigator	OR is defined as the number of participants with either a confirmed complete response (CR; disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of the LD of the target lesions, compared with the baseline sum LD). CR and PR were assessed per Response Evaluation Criteria in Solid Tumors (RECIST). To be assigned a status of PR or CR, a confirmatory disease assessment was to be performed 28 days (4 weeks) or greater after the criteria for response were first met. In addition, a bone scan must have been obtained to rule out the presence of new bone lesions or progression of existing bone lesions, even if the participant had no bone lesions present at Baseline. If a bone scan was performed at the time of initial response or near the time of response, the bone scan did not need to be repeated.	From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
Secondary	Number of Participants With Clinical Benefit (CB)	CB is defined as the number of participants with evidence of confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of the target lesions, compared with the baseline sum LD) at any time or stable disease (SD, neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD [defined as at least a 20% increase in the sum of the LD of target lesions, compared with the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions] based on investigator assessment), for at least 24 weeks.	From randomization until disease progression, death, or discontinuation from the study (average of 10 months). Cut-off 11-Jun-2012
Secondary	Duration of Response	Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of the target lesions, compared with the baseline sum LD) until the first documented sign of PD (at least a 20% increase in the sum of the LD of target lesions, compared with the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions) or death due to breast cancer. In the absence of confirmation of death, survival time was to be censored at the time of the last investigator contact.	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
Secondary	Number of Participants With CNS Progression at Any Time	CNS progression was documented by a brain scan and was indicated by the investigator on the follow-up electronic Case Report Form. CNS relapse is defined as the appearance of >=1 enhancing lesion measuring >=6 mm on T1W MRI without CNS symptoms that were considered to be unequivocal based on all relevant radiological features (e.g., associated T2W signal abnormality); the appearance of any enhancing lesion on T1W MRI with CNS symptoms; unequivocal finding of leptomeningeal disease, with or without symptoms; and unequivocal finding of multifocal intraparenchymal lesions with or without symptoms. In the event of the appearance of a <6 mm lesions(s) without CNS lesions, or equivocal findings potentially suggesting leptomeningeal disease, these findings were followed with a subsequent scan within 6 weeks. If unequivocal progression was determined with the subsequent scan and/or CNS symptoms occurred, then CNS relapse crieria were met.	From the time of randomization until death due to any cause (average of 10 months). Cut-off 11-Jun-2012
Secondary	Number of Participants With Qualitative and Quantitative Toxicities	Qualitative and quantitative toxicities were measured as AEs. See the outcome measure entitled "Number of participants with the indicated Grade 3 or Grade 4 Adverse Events (AEs) occurring in >=2 participants in either treatment arm" and the AE module of this results summary for a list of AEs occurring in the study. An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.	From the first dose of study medication until 30 days after the last dose of study treatment (average of 10 months)
Secondary	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	Because the study terminated early, pharmacogenetic and biomarker analyses were not performed.	Baseline
Secondary	Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events (AEs) Occurring in >=2% of Participants in Either Treatment Arm	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The Investigator assessed whether the AE was related to study drug. AEs were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0=No AE or within normal limits; 1=Mild AE; 2=Moderate AE; 3=Severe and undesirable AE; 4=Life-threatening or disabling AE; 5=Death related to AE.	From the first dose of study medication until 30 days after the last dose of study treatment (average of 10 months).