Clinical trial NCT00968968: Continued HER2 Suppression With Lapatinib Plus Trastuzumab Versus Trastuzumab Alone
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cancer
Keywords: carcinoma, breast lump, Pagets disease, breast cancer positive for human epidermal growth factor receptor 2, breast cancer progression, estrogen-receptor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-08-31
Enrollment: 37
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Progression-free Survival
timeFrame: Time from randomization until disease progression or death, approximately 4 years
Secondary outcomes:
measure: Overall Survival
timeFrame: Time from randomization until death, approximately 4 years
measure: Best Overall Response
timeFrame: approximately 4 years
measure: Clinical Benefit Response Rate (CR, PR or SD ≥24 Weeks)
timeFrame: approximately 4 years
measure: Adverse Event Profile of the Two Treatment Arms
timeFrame: From first dose of study treatment until 30 days after the last dose of study treatment, approximately 8 years.
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Flagstaff
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Gilbert
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Mesa
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Mesa
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Sedona
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Tucson
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Bakersfield
country: United States
facility: Novartis Investigative Site
state: California
city: Beverly Hills
country: United States
facility: Novartis Investigative Site
state: California
city: Fullerton
country: United States
facility: Novartis Investigative Site
state: California
city: La Jolla
country: United States
facility: Novartis Investigative Site
state: California
city: La Jolla
country: United States
facility: Novartis Investigative Site
state: California
city: Long Beach
country: United States
facility: Novartis Investigative Site
state: California
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: San Diego
country: United States
facility: Novartis Investigative Site
state: California
city: San Pablo
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Maria
country: United States
facility: Novartis Investigative Site
state: California
city: Hollywood
country: United States
facility: Novartis Investigative Site
state: Florida
city: Hudson
country: United States
facility: Novartis Investigative Site
state: Florida
city: New Port Richey
country: United States
facility: Novartis Investigative Site
state: Florida
city: Augusta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Augusta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Dublin
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Arlington Heights
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Evanston
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Glenview
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Highland Park
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Joliet
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Niles
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Peoria
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Peoria
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Peoria
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Skokie
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Winfield
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Goshen
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Mishawaka
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Columbia
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Silver Spring
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Brownstown
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Dearborn
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: West Bloomfield
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Burnsville
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Coon Rapids
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Edina
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Fridley
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Maplewood
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Minneapolis
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Saint Paul
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Woodbury
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Columbia
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Jefferson City
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Billings
country: United States
facility: Novartis Investigative Site
state: Montana
city: Henderson
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Henderson
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Las Vegas
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Las Vegas
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Las Vegas
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Cary
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Elizabeth City
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Greensboro
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Raleigh
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Raleigh
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Washington
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Abington
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Radnor
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Abilene
country: United States
facility: Novartis Investigative Site
state: Texas
city: Beaumont
country: United States
facility: Novartis Investigative Site
state: Texas
city: Bedford
country: United States
facility: Novartis Investigative Site
state: Texas
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: El Paso
country: United States
facility: Novartis Investigative Site
state: Texas
city: El Paso
country: United States
facility: Novartis Investigative Site
state: Texas
city: Fort Worth
country: United States
facility: Novartis Investigative Site
state: Texas
city: Fort Worth
country: United States
facility: Novartis Investigative Site
state: Texas
city: Garland
country: United States
facility: Novartis Investigative Site
state: Texas
city: Grapevine
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Kerrville
country: United States
facility: Novartis Investigative Site
state: Texas
city: Odessa
country: United States
facility: Novartis Investigative Site
state: Texas
city: Plano
country: United States
facility: Novartis Investigative Site
state: Texas
city: Plano
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Bountiful
country: United States
facility: Novartis Investigative Site
state: Utah
city: Layton
country: United States
facility: Novartis Investigative Site
state: Utah
city: Murray
country: United States
facility: Novartis Investigative Site
state: Utah
city: Provo
country: United States
facility: Novartis Investigative Site
state: Utah
city: Salt Lake City
country: United States
facility: Novartis Investigative Site
state: Utah
city: Salt Lake City
country: United States
facility: Novartis Investigative Site
state: Utah
city: Sandy
country: United States
facility: Novartis Investigative Site
state: Utah
city: Arlington
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Chesapeake
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Fairfax
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Gainesville
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Hampton
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Leesburg
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Newport News
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Norfolk
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Virginia Beach
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Williamsburg
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Edmonds
country: United States
facility: Novartis Investigative Site
state: Washington
city: Federal Way
country: United States
facility: Novartis Investigative Site
state: Washington
city: Gig Harbor
country: United States
facility: Novartis Investigative Site
state: Washington
city: Lakewood
country: United States
facility: Novartis Investigative Site
state: Washington
city: Puyallup
country: United States
facility: Novartis Investigative Site
state: Washington
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Tacoma
country: United States
facility: Novartis Investigative Site
state: Washington
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: Brampton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Oshawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Rimouski
country: Canada
facility: Novartis Investigative Site
state: Quebec
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: