A Study to Compare the Safety and Efficacy of an Aromatase Inhibitor in Combination With Lapatinib, Trastuzumab or Both for the Treatment of Hormone Receptor Positive, HER2+ Metastatic Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01160211
First received: July 1, 2010
Last updated: September 11, 2014
Last verified: September 2014
  Purpose

A study to compare the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor positive, HER2+ metastatic breast cancer (MBC).


Condition Intervention Phase
Neoplasms, Breast
Drug: lapatinib
Drug: trastuzumab
Drug: Aromatase inhibitor
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Trial to Compare the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus an Aromatase Inhibitor (AI) vs. Trastuzumab Plus an AI vs. Lapatinib Plus an AI as 1st- or 2nd- Line Therapy in Postmenopausal Subjects With Hormone Receptor+, HER2+ Metastatic Breast Cancer (MBC) Who Received Prior Trastuzumab and Endocrine Therapies

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Overall survival of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination [ Time Frame: approximately 6 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival of trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI [ Time Frame: approximately 6 years ] [ Designated as safety issue: No ]
  • Progression free survival (PFS) of lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ] [ Designated as safety issue: No ]
  • Overall response rate (complete or partial response), time to response, and duration of response in lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ] [ Designated as safety issue: No ]
  • Clinical benefit (complete response, partial response, or stable disease for at least 6 months) of lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ] [ Designated as safety issue: No ]
  • Safety and tolerability of all three treatment groups (lapatinib/ trastuzumab/ AI, trastuzumab/ AI, or lapatinib/AI) [ Time Frame: approximately 6 years ] [ Designated as safety issue: No ]
  • Changes in the quality of life (QoL) status relative to baseline of lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ] [ Designated as safety issue: No ]
  • The identification of tumor-derived biomarkers (DNA, RNA and protein) associated with clinical outcome [ Designated as safety issue: No ]
  • The evaluation of biomarkers known to predict sensitivity or resistance to lapatinib and trastuzumab (e.g. p95HER2, PIK3CA mutations, PTEN aberrations and other markers associated with these pathways) and determine the relationship with clinical outcom [ Designated as safety issue: No ]
  • The examination of pre and post treatment circulating free DNA (cfDNA) to determine whether mutations (e.g., PI3KCA) in cfDNA correlate with that in the tumor tissue from which it is derived [ Designated as safety issue: No ]
  • Dependent on study outcomes, exploratory research may be conducted to identify genetic markers in patient DNA that are associated with response to study drugs. [ Designated as safety issue: No ]

Estimated Enrollment: 525
Study Start Date: May 2011
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lapatinib plus trastuzumab plus aromatase inhibitor
Experimental
Drug: lapatinib
1000 mg by mouth once a day
Drug: trastuzumab
Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks
Drug: Aromatase inhibitor
Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily
Active Comparator: trastuzmab plus aromatase inhibitor
Active Comparator
Drug: trastuzumab
Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks
Drug: Aromatase inhibitor
Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily
Active Comparator: lapatinib plus aromatase inhibitor
Active Comparator
Drug: Aromatase inhibitor
Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily
Drug: lapatinib
1500 mg by mouth once daily

Detailed Description:

This is a Phase III, randomized, open-label, multi-center, three arm study of lapatinib plus trastuzumab plus an aromatase inhibitor (AI), trastuzumab plus an AI, or lapatinib plus an AI to evaluate the efficacy and safety of these regimens as first- or second-line therapy in postmenopausal subjects with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) who have received prior trastuzumab and endocrine therapies. Eligible subjects will be postmenopausal; have tumors that are ER and/or PgR positive and HER2-positive; have Stage IV metastatic breast cancer. The primary objective is to demonstrate superiority of lapatinib/trastuzumab/AI combination versus (vs.) trastuzumab/AI combination for overall survival. The secondary objectives are to evaluate overall survival in trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI, progression free survival, overall response rate, clinical benefit rate, the safety and tolerability of all three treatment groups (lapatinib plus trastuzumab plus an AI, trastuzumab plus an AI, or lapatinib plus an AI), and quality of life status relative to baseline.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Subjects eligible for enrollment in the study must meet all of the following criteria:

  1. Signed written informed consent. In Korea and Japan, subjects who are between >=18 and <20 years of age must also have a legal representative sign the written informed consent.
  2. Post-menopausal female subjects >=18 years of age. Post-menopausal as defined by any of the following:

    • Subjects at least 60 years of age.
    • Subjects under 60 years of age and amenorrhic for at least 12 consecutive months AND follicle-stimulating hormone (FSH) and estradiol levels in postmenopausal range (utilizing ranges from the local laboratory facility).
    • Prior bilateral oophorectomy.
    • Prior radiation castration with amenorrhea for at least 6 months
  3. Subjects must have a history of histologically confirmed breast cancer, with a clinically confirmed diagnosis of metastatic disease [confirmed by histology, cytology or other clinical means (e.g. CT, MRI)]. Subjects may have either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
  4. Tumors that are ER+ and/or PgR+ by local laboratory
  5. Documentation of HER2 overexpression or gene amplification, in the invasive component of either the primary tumor or metastatic disease site as defined as:

    • 3+ by Immunohistochemistry (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 test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0]
  6. Subject must have received at least one prior regimen containing trastuzumab in combination with chemotherapy for breast cancer:.

    • Subject has ONLY received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment. OR
    • Subject has received ONE prior trastuzumab-containing regimen for metastatic disease (and has progressed), and may or may not have received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment.
  7. Subject must have received prior endocrine therapy (such as aromatase inhibitors or selective estrogen receptor modulators). 8. Subjects who have a life expectancy of > 6 months as assessed by the treating investigator

9. Subjects must have baseline Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA) 10. Subject must have an ECOG performance status of 0-1 11. All prior treatment related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 at the time of randomization 12. Completion of screening assessments 13. Adequate baseline organ function. 14. Subjects must meet all of the following criteria:

  • QTc <450msec or
  • QTc <480msec for subjects with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB) or to Fridericia's formula (QTcF), machine or manual over read, for males and females. The specific formula that will be used in a protocol should be determined prior to initiation of the study, and the formula used to determine inclusion and discontinuation should be the same throughout the study. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period

Exclusion criteria:

  1. History of another malignancy. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
  2. Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor, or the disease is considered by the investigator to be rapidly progressing or life threatening (subjects who are intended for chemotherapy)
  3. Serious cardiac illness or medical condition including but not confined to:

    • Uncontrolled arrhythmias
    • Uncontrolled or symptomatic angina
    • History of congestive heart failure (CHF)
    • Documented myocardial infarction <6 months from study entry
  4. Known history of, or clinical evidence of, central nervous system (CNS) metastases or leptomeningeal carcinomatosis
  5. Have acute or currently 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)
  6. Have a 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)
  7. Have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  8. Have a 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, contraindicates their participation
  9. Any prohibited medication.
  10. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01160211

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

  Show 206 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01160211     History of Changes
Other Study ID Numbers: 114299
Study First Received: July 1, 2010
Last Updated: September 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
1st line MBC
MBC
hormone receptor positive
lapatinib
trastuzumab
HER2 positive
aromatase inhibitor

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Hormones
Trastuzumab
Lapatinib
Aromatase Inhibitors
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014