Continued HER2 Suppression With Lapatinib Plus Trastuzumab Versus Trastuzumab Alone

Cancer Clinical Trial

Official title:

A Randomized, Phase III, Open-label Study of Lapatinib Plus Trastuzumab Versus Trastuzumab as Continued HER2 Suppression Therapy After Completion of First- or Second-line Trastuzumab Plus Chemotherapy in Subjects With HER2-positive Metastatic Breast Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00968968
• Other study ID #: 112515
• Secondary ID: CLAP016A2306
• Status: Terminated
• Phase: Phase 3
• Start date: January 20, 2010
• Est. completion date: March 30, 2018

Study information

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

Clinical Trial Summary

This was a randomized, open-label, multi-center Phase III study evaluating the efficacy and safety of lapatinib in combination with trastuzumab versus trastuzumab alone as continued HER2 suppression therapy in women with HER2-positive metastatic breast cancer (MBC). Eligible subjects should have completed 12 to 24 weeks of first- or second-line treatment with trastuzumab plus chemotherapy, experienced either complete disappearance of all metastatic lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions, and been indicated to continue to receive trastuzumab alone as maintenance therapy. Eligible subjects who entered the LPT112515 study on first-line treatment should not have known history of central nervous system (CNS) metastases; subjects who entered the study on second-line treatment should not have known history of CNS metastases or have stable (asymptomatic and off steroids ≥3 months) CNS metastases. The primary objective of this study was to compare progression-free survival (PFS) in subjects with HER2-positive MBC randomized to receive treatment with lapatinib plus trastuzumab versus those randomized to receive trastuzumab alone. The secondary objectives included overall survival, clinical benefit response rate (CR, PR or SD ≥24 weeks) and the qualitative and quantitative adverse event profile of the 2 treatment arms. It was estimated that 280 subjects (140 per group) would be required to observe 193 PFS events.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 37
• Est. completion date: March 30, 2018
• Est. primary completion date: February 21, 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed the informed consent form (ICF)

• Female, =18 years of age

• Histologically verified breast cancer with distant metastases (metastatic breast cancer)

• Documentation of HER2 overexpression or gene amplification in the invasive component of either the primary tumor or metastatic disease site defined as:

• 3+ by IHC and/or

• HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH HER2 gene copies to chromosome 17 signal ratio of =2.0]

• Completed 12 to 24 weeks of first- or second-line treatment with trastuzumab in combination with chemotherapy

• Either complete disappearance of all lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions

• Documentation of lesion response during the course of therapy received prior to randomization (i.e., improvement or no worsening of tumor burden; the absence of new lesions)

• Measurable disease is not required for study participation

• No known or suspected (associated neurological signs and symptoms) brain metastases (including leptomeningeal involvement)

• Stable brain metastasis (defined as asymptomatic and off steroids =3 months) are permitted in subjects on second-line treatment (completed 12-24 weeks of second-line treatment with trastuzumab plus chemotherapy)

• Baseline of Left Ventricular Ejection Fraction (LVEF) =50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA)

• Completion of screening assessments

• Have adequate marrow and organ function

Exclusion Criteria:

• History of other malignancy. Subjects who have been disease-free for 5 years or subjects with a history of completely resected non-melanoma skin cancer (basal or squamous) are eligible

• Eastern Cooperative Oncology Group (ECOG) Performance Status >2

• Concurrent anti-cancer treatment, except anti-hormonal therapy for subjects with hormone receptor positive breast cancer

• Concurrent treatment with an investigational agent

• Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib

• Concurrent treatment with protocol-defined prohibited medications (refer to protocol for details)

• Serious cardiac illness or medical condition including but not confined to:

• Uncontrolled arrhythmias

• Uncontrolled or symptomatic angina

• History of congestive heart failure (CHF)

• Myocardial infarction <6 months from study entry

• Acute or current active (requiring anti-viral therapy) hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)

• Concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent)

• Women of childbearing potential, including women whose last menstrual period was <12 months ago (unless surgically sterile) who are unable or unwilling to use adequate contraceptive measures during the study treatment period. Adequate contraception includes intra-uterine device, barrier methods with spermicide, or oral contraceptives (unless clinically contraindicated for the subject population or per local practice, refer to protocol for further details)

• Pregnant or lactating females

• Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor , contra-indicates participation

Related Conditions & MeSH terms

• Cancer

Intervention

Drug:
• Lapatinib
Oral Lapatinib 1000 mg once daily. Lapatinib was a small molecule, reversible inhibitor targeting HER2 tyrosine kinase receptor.

Biological:
• Trastuzumab
IV Trastuzumab 6 mg/kg every three weeks. Trastuzumab was a humanized, monoclonal antibody directed against the extracellular domain of the HER2 tyrosine kinase receptor.

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Brampton	Ontario
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	Oshawa	Ontario
Canada	Novartis Investigative Site	Rimouski	Quebec
United States	Novartis Investigative Site	Abilene	Texas
United States	Novartis Investigative Site	Abington	Pennsylvania
United States	Novartis Investigative Site	Arlington	Virginia
United States	Novartis Investigative Site	Arlington Heights	Illinois
United States	Novartis Investigative Site	Augusta	Georgia
United States	Novartis Investigative Site	Augusta	Georgia
United States	Novartis Investigative Site	Bakersfield	California
United States	Novartis Investigative Site	Beaumont	Texas
United States	Novartis Investigative Site	Bedford	Texas
United States	Novartis Investigative Site	Beverly Hills	California
United States	Novartis Investigative Site	Billings	Montana
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Bountiful	Utah
United States	Novartis Investigative Site	Brownstown	Michigan
United States	Novartis Investigative Site	Burnsville	Minnesota
United States	Novartis Investigative Site	Cary	North Carolina
United States	Novartis Investigative Site	Chandler	Arizona
United States	Novartis Investigative Site	Chesapeake	Virginia
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Columbia	Maryland
United States	Novartis Investigative Site	Columbia	Missouri
United States	Novartis Investigative Site	Coon Rapids	Minnesota
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dearborn	Michigan
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Dublin	Georgia
United States	Novartis Investigative Site	Edina	Minnesota
United States	Novartis Investigative Site	Edmonds	Washington
United States	Novartis Investigative Site	El Paso	Texas
United States	Novartis Investigative Site	El Paso	Texas
United States	Novartis Investigative Site	Elizabeth City	North Carolina
United States	Novartis Investigative Site	Evanston	Illinois
United States	Novartis Investigative Site	Fairfax	Virginia
United States	Novartis Investigative Site	Federal Way	Washington
United States	Novartis Investigative Site	Flagstaff	Arizona
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Fridley	Minnesota
United States	Novartis Investigative Site	Fullerton	California
United States	Novartis Investigative Site	Gainesville	Virginia
United States	Novartis Investigative Site	Garland	Texas
United States	Novartis Investigative Site	Gig Harbor	Washington
United States	Novartis Investigative Site	Gilbert	Arizona
United States	Novartis Investigative Site	Glenview	Illinois
United States	Novartis Investigative Site	Goshen	Indiana
United States	Novartis Investigative Site	Grapevine	Texas
United States	Novartis Investigative Site	Greensboro	North Carolina
United States	Novartis Investigative Site	Hampton	Virginia
United States	Novartis Investigative Site	Henderson	Nevada
United States	Novartis Investigative Site	Henderson	Nevada
United States	Novartis Investigative Site	Highland Park	Illinois
United States	Novartis Investigative Site	Hollywood	Florida
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Hudson	Florida
United States	Novartis Investigative Site	Jefferson City	Missouri
United States	Novartis Investigative Site	Joliet	Illinois
United States	Novartis Investigative Site	Kerrville	Texas
United States	Novartis Investigative Site	La Jolla	California
United States	Novartis Investigative Site	La Jolla	California
United States	Novartis Investigative Site	Lakewood	Washington
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Layton	Utah
United States	Novartis Investigative Site	Leesburg	Virginia
United States	Novartis Investigative Site	Long Beach	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Maplewood	Minnesota
United States	Novartis Investigative Site	Mesa	Arizona
United States	Novartis Investigative Site	Mesa	Arizona
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Mishawaka	Indiana
United States	Novartis Investigative Site	Murray	Utah
United States	Novartis Investigative Site	New Port Richey	Florida
United States	Novartis Investigative Site	Newport News	Virginia
United States	Novartis Investigative Site	Niles	Illinois
United States	Novartis Investigative Site	Norfolk	Virginia
United States	Novartis Investigative Site	Odessa	Texas
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Plano	Texas
United States	Novartis Investigative Site	Plano	Texas
United States	Novartis Investigative Site	Provo	Utah
United States	Novartis Investigative Site	Puyallup	Washington
United States	Novartis Investigative Site	Radnor	Pennsylvania
United States	Novartis Investigative Site	Raleigh	North Carolina
United States	Novartis Investigative Site	Raleigh	North Carolina
United States	Novartis Investigative Site	Saint Paul	Minnesota
United States	Novartis Investigative Site	Salt Lake City	Utah
United States	Novartis Investigative Site	Salt Lake City	Utah
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Pablo	California
United States	Novartis Investigative Site	Sandy	Utah
United States	Novartis Investigative Site	Santa Maria	California
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Sedona	Arizona
United States	Novartis Investigative Site	Silver Spring	Maryland
United States	Novartis Investigative Site	Skokie	Illinois
United States	Novartis Investigative Site	Tacoma	Washington
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Virginia Beach	Virginia
United States	Novartis Investigative Site	Washington	North Carolina
United States	Novartis Investigative Site	West Bloomfield	Michigan
United States	Novartis Investigative Site	Williamsburg	Virginia
United States	Novartis Investigative Site	Winfield	Illinois
United States	Novartis Investigative Site	Woodbury	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival	Progression-free survival (PFS) with lapatinib plus trastuzumab versus trastuzumab alone.; Progression-free survival (PFS) is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to last contact date up to 21Feb2014.; Disease Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1), a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum diameters recorded since the treatment started (the sum must have an absolute increase from nadir of 5mm), or an unequivocal progression of existing non-target lesions, or the appearance of new lesions.	Time from randomization until disease progression or death, approximately 4 years
Secondary	Overall Survival	Overall Survival is defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.	Time from randomization until death, approximately 4 years
Secondary	Best Overall Response	The best overall response was the best response from the start of the treatment until disease progression/recurrence and was determined programmatically using investigators assessment of responses of target lesion, non-target lesion and new lesions based on RECIST v1.1. Complete Response (CR) = disappearance of all target lesion and non-target lesions if applicable, and no new lesion; Partial Response (PR) = =30% decrease in the sum of the longest diameter of target lesions and non-target lesion was neither complete response nor progressive disease (Non-CR/Non-PD) or not evaluable (NE); SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD = = 20% increase from nadir of the target lesions or appearance of new lesion. CR and PR were confirmed responses. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.	approximately 4 years
Secondary	Clinical Benefit Response Rate (CR, PR or SD =24 Weeks)	Clinical Benefit Rate (CBR) was defined as the percentage of patients achieving either a confirmed CR or PR at any time or maintaining SD for at least 24 weeks while on study, according to the investigator assessment of response per RECIST 1.1 criteria.; Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.	approximately 4 years
Secondary	Adverse Event Profile of the Two Treatment Arms		From first dose of study treatment until 30 days after the last dose of study treatment, approximately 8 years.