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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01160211
Recruitment Status : Active, not recruiting
First Posted : July 12, 2010
Last Update Posted : June 7, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE July 1, 2010
First Posted Date  ICMJE July 12, 2010
Last Update Posted Date June 7, 2018
Actual Study Start Date  ICMJE May 5, 2011
Actual Primary Completion Date March 11, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 15, 2016)
Progression free survival (PFS) of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination [ Time Frame: approximately 6 years ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 8, 2010)
To demonstrate superiority of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination for overall survival (OS) [ Time Frame: approximately 6 years ]
Change History Complete list of historical versions of study NCT01160211 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 15, 2016)
  • Progression free survival (PFS) of trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI [ Time Frame: approximately 6 years ]
  • Overall survival (OS) of lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ]
  • 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 ]
  • 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 ]
  • Safety and tolerability of all three treatment groups (lapatinib/ trastuzumab/ AI, trastuzumab/ AI, or lapatinib/AI) [ Time Frame: approximately 6 years ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2010)
  • To compare OS in trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI [ Time Frame: approximately 6 years ]
  • To compare progression free survival (PFS) in lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ]
  • To compare 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 ]
  • To compare clinical benefit (complete response, partial response, or stable disease for at least 6 months) in lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ]
  • To evaluate the safety and tolerability of all three treatment groups (lapatinib/ trastuzumab/ AI, trastuzumab/ AI, or lapatinib/AI) [ Time Frame: approximately 6 years ]
  • To compare lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI with respect to change in quality of life (QoL) status relative to baseline [ Time Frame: approximately 6 years ]
  • • To identify tumor-derived biomarkers (DNA, RNA and protein) associated with clinical outcome
  • To evaluate 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 outcome
  • To examine 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
  • Dependent on study outcomes, exploratory research may be conducted to identify genetic markers in patient DNA that are associated with response to study drugs.
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary 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).
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 progression free survival. The secondary objectives are to evaluate progression free survival in trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI, overall 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.
Study Type  ICMJE Interventional
Study Phase Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms, Breast
Intervention  ICMJE
  • 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
  • Drug: lapatinib
    1500 mg by mouth once daily
Study Arms
  • Experimental: Lapatinib plus trastuzumab plus aromatase inhibitor
    Experimental
    Interventions:
    • Drug: lapatinib
    • Drug: trastuzumab
    • Drug: Aromatase inhibitor
  • Active Comparator: trastuzmab plus aromatase inhibitor
    Active Comparator
    Interventions:
    • Drug: trastuzumab
    • Drug: Aromatase inhibitor
  • Active Comparator: lapatinib plus aromatase inhibitor
    Active Comparator
    Interventions:
    • Drug: Aromatase inhibitor
    • Drug: lapatinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 30, 2017)
364
Original Estimated Enrollment  ICMJE
 (submitted: July 8, 2010)
525
Estimated Study Completion Date May 5, 2019
Actual Primary Completion Date March 11, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender
Sexes Eligible for Study: Female
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Brazil,   Bulgaria,   Canada,   China,   Colombia,   Croatia,   France,   Germany,   Greece,   Hong Kong,   Hungary,   India,   Ireland,   Israel,   Italy,   Japan,   Korea, Republic of,   Lithuania,   Mexico,   Norway,   Peru,   Philippines,   Poland,   Portugal,   Puerto Rico,   Romania,   Russian Federation,   Serbia,   Singapore,   South Africa,   Spain,   Taiwan,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01160211
Other Study ID Numbers  ICMJE 114299
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP