Continued HER2 Suppression With Lapatinib Plus Trastuzumab Versus Trastuzumab Alone

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

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.

Study Overview

• Status: Terminated
• Conditions: Cancer
• Intervention / Treatment: Drug: Lapatinib; Biological: Trastuzumab

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Novartis Investigative Site
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • Novartis Investigative Site
    • Oshawa, Ontario, Canada, L1G 2B9
      • Novartis Investigative Site
  • Quebec
    • Rimouski, Quebec, Canada, G5L 5T1
      • Novartis Investigative Site
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Novartis Investigative Site
    • Flagstaff, Arizona, United States, 86001
      • Novartis Investigative Site
    • Gilbert, Arizona, United States, 85297
      • Novartis Investigative Site
    • Mesa, Arizona, United States, 85206
      • Novartis Investigative Site
    • Mesa, Arizona, United States, 85202
      • Novartis Investigative Site
    • Sedona, Arizona, United States, 86336
      • Novartis Investigative Site
    • Tucson, Arizona, United States, 85724
      • Novartis Investigative Site
  • California
    • Bakersfield, California, United States, 93309
      • Novartis Investigative Site
    • Beverly Hills, California, United States, 90211
      • Novartis Investigative Site
    • Fullerton, California, United States, 92835
      • Novartis Investigative Site
    • La Jolla, California, United States, 92093-0987
      • Novartis Investigative Site
    • La Jolla, California, United States, 92037
      • Novartis Investigative Site
    • Long Beach, California, United States, 90813
      • Novartis Investigative Site
    • Los Angeles, California, United States, 90095- 7187
      • Novartis Investigative Site
    • San Diego, California, United States, 92103-8411
      • Novartis Investigative Site
    • San Pablo, California, United States, 94806
      • Novartis Investigative Site
    • Santa Maria, California, United States, 93454
      • Novartis Investigative Site
  • Florida
    • Hollywood, Florida, United States, 33021
      • Novartis Investigative Site
    • Hudson, Florida, United States, 34667
      • Novartis Investigative Site
    • New Port Richey, Florida, United States, 34655
      • Novartis Investigative Site
  • Georgia
    • Augusta, Georgia, United States, 30901
      • Novartis Investigative Site
    • Augusta, Georgia, United States, 30909
      • Novartis Investigative Site
    • Dublin, Georgia, United States, 31021
      • Novartis Investigative Site
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Novartis Investigative Site
    • Chicago, Illinois, United States, 60611
      • Novartis Investigative Site
    • Evanston, Illinois, United States, 60201
      • Novartis Investigative Site
    • Glenview, Illinois, United States, 60025
      • Novartis Investigative Site
    • Highland Park, Illinois, United States, 60035
      • Novartis Investigative Site
    • Joliet, Illinois, United States, 60435
      • Novartis Investigative Site
    • Niles, Illinois, United States, 60714
      • Novartis Investigative Site
    • Peoria, Illinois, United States, 61615
      • Novartis Investigative Site
    • Peoria, Illinois, United States, 61637
      • Novartis Investigative Site
    • Peoria, Illinois, United States, 61636
      • Novartis Investigative Site
    • Skokie, Illinois, United States, 60076
      • Novartis Investigative Site
    • Winfield, Illinois, United States, 60190
      • Novartis Investigative Site
  • Indiana
    • Goshen, Indiana, United States, 46526
      • Novartis Investigative Site
    • Mishawaka, Indiana, United States, 46545
      • Novartis Investigative Site
  • Maryland
    • Columbia, Maryland, United States, 21044
      • Novartis Investigative Site
    • Silver Spring, Maryland, United States, 20910
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Novartis Investigative Site
    • Boston, Massachusetts, United States, 02215
      • Novartis Investigative Site
  • Michigan
    • Brownstown, Michigan, United States, 48183
      • Novartis Investigative Site
    • Dearborn, Michigan, United States, 48126
      • Novartis Investigative Site
    • Detroit, Michigan, United States, 48202
      • Novartis Investigative Site
    • West Bloomfield, Michigan, United States, 48322
      • Novartis Investigative Site
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Novartis Investigative Site
    • Coon Rapids, Minnesota, United States, 55433
      • Novartis Investigative Site
    • Edina, Minnesota, United States, 55435
      • Novartis Investigative Site
    • Fridley, Minnesota, United States, 55432
      • Novartis Investigative Site
    • Maplewood, Minnesota, United States, 55109
      • Novartis Investigative Site
    • Minneapolis, Minnesota, United States, 55404
      • Novartis Investigative Site
    • Saint Paul, Minnesota, United States, 55102
      • Novartis Investigative Site
    • Woodbury, Minnesota, United States, 55125
      • Novartis Investigative Site
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Novartis Investigative Site
    • Jefferson City, Missouri, United States, 65109
      • Novartis Investigative Site
  • Montana
    • Billings, Montana, United States, 59102
      • Novartis Investigative Site
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Novartis Investigative Site
    • Henderson, Nevada, United States, 89074
      • Novartis Investigative Site
    • Las Vegas, Nevada, United States, 89169
      • Novartis Investigative Site
    • Las Vegas, Nevada, United States, 89148
      • Novartis Investigative Site
    • Las Vegas, Nevada, United States, 89128
      • Novartis Investigative Site
  • North Carolina
    • Cary, North Carolina, United States, 27518
      • Novartis Investigative Site
    • Elizabeth City, North Carolina, United States, 27909
      • Novartis Investigative Site
    • Greensboro, North Carolina, United States, 27403
      • Novartis Investigative Site
    • Raleigh, North Carolina, United States, 27607
      • Novartis Investigative Site
    • Raleigh, North Carolina, United States, 27614
      • Novartis Investigative Site
    • Washington, North Carolina, United States, 27889
      • Novartis Investigative Site
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Novartis Investigative Site
    • Philadelphia, Pennsylvania, United States, 19106
      • Novartis Investigative Site
    • Radnor, Pennsylvania, United States, 19087
      • Novartis Investigative Site
  • Texas
    • Abilene, Texas, United States, 79606-5208
      • Novartis Investigative Site
    • Beaumont, Texas, United States, 77701
      • Novartis Investigative Site
    • Bedford, Texas, United States, 76022
      • Novartis Investigative Site
    • Dallas, Texas, United States, 75230
      • Novartis Investigative Site
    • El Paso, Texas, United States, 79902
      • Novartis Investigative Site
    • El Paso, Texas, United States, 79915
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76104
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76132
      • Novartis Investigative Site
    • Garland, Texas, United States, 75042
      • Novartis Investigative Site
    • Grapevine, Texas, United States, 76051
      • Novartis Investigative Site
    • Houston, Texas, United States, 77024
      • Novartis Investigative Site
    • Kerrville, Texas, United States, 78028
      • Novartis Investigative Site
    • Odessa, Texas, United States, 79761
      • Novartis Investigative Site
    • Plano, Texas, United States, 75093
      • Novartis Investigative Site
    • Plano, Texas, United States, 75075
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78217
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78258-3912
      • Novartis Investigative Site
  • Utah
    • Bountiful, Utah, United States, 84010
      • Novartis Investigative Site
    • Layton, Utah, United States, 84041
      • Novartis Investigative Site
    • Murray, Utah, United States, 84157-7000
      • Novartis Investigative Site
    • Provo, Utah, United States, 84604
      • Novartis Investigative Site
    • Salt Lake City, Utah, United States, 84106
      • Novartis Investigative Site
    • Salt Lake City, Utah, United States, 84102
      • Novartis Investigative Site
    • Sandy, Utah, United States, 84094
      • Novartis Investigative Site
  • Virginia
    • Arlington, Virginia, United States, 22205
      • Novartis Investigative Site
    • Chesapeake, Virginia, United States, 23320
      • Novartis Investigative Site
    • Fairfax, Virginia, United States, 22031
      • Novartis Investigative Site
    • Gainesville, Virginia, United States, 20155
      • Novartis Investigative Site
    • Hampton, Virginia, United States, 23666
      • Novartis Investigative Site
    • Leesburg, Virginia, United States, 20176
      • Novartis Investigative Site
    • Newport News, Virginia, United States, 23606
      • Novartis Investigative Site
    • Norfolk, Virginia, United States, 23502
      • Novartis Investigative Site
    • Virginia Beach, Virginia, United States, 23456
      • Novartis Investigative Site
    • Williamsburg, Virginia, United States, 23185
      • Novartis Investigative Site
  • Washington
    • Edmonds, Washington, United States, 98026
      • Novartis Investigative Site
    • Federal Way, Washington, United States, 98003
      • Novartis Investigative Site
    • Gig Harbor, Washington, United States, 98332
      • Novartis Investigative Site
    • Lakewood, Washington, United States, 98499
      • Novartis Investigative Site
    • Puyallup, Washington, United States, 98372
      • Novartis Investigative Site
    • Seattle, Washington, United States, 98104
      • Novartis Investigative Site
    • Seattle, Washington, United States, 98133
      • Novartis Investigative Site
    • Tacoma, Washington, United States, 98405
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Lapatinib plus Trastuzumab	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.
Active Comparator: Arm 2: Trastuzumab	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2010
• Primary Completion (Actual): February 21, 2014
• Study Completion (Actual): March 30, 2018

Study Registration Dates

• First Submitted: August 27, 2009
• First Submitted That Met QC Criteria: August 27, 2009
• First Posted (Estimate): August 31, 2009

Study Record Updates

• Last Update Posted (Actual): June 10, 2019
• Last Update Submitted That Met QC Criteria: June 5, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: carcinoma, breast lump, Pagets disease, breast cancer positive for human epidermal growth factor receptor 2, breast cancer progression, estrogen-receptor
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Trastuzumab; Lapatinib
• Other Study ID Numbers: 112515; CLAP016A2306 (Other Identifier: Novartis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No