Study Comparing Lapatinib (GW572016) And Letrozole Versus Letrozole In Subjects With Advanced Or Metastatic Breast Cancer

Study Overview
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Brief Summary
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This study evaluated and compared the efficacy and tolerability of lapatinib and letrozole, with letrozole and placebo in post-menopausal women with hormone receptor positive (ER positive and/or PgR positive) advanced or metastatic breast cancer, who had not received prior therapy for advanced or metastatic disease.

Detailed Description
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Subjects were randomly assigned to receive either lapatinib (1500 mg once daily orally) with letrozole (2.5 mg once daily orally), or letrozole (2.5 mg once daily orally) with placebo (which matched with lapatinib tablet). Randomization was stratified by site of disease (i.e., soft tissue/visceral disease versus bone only disease) and time since prior adjuvant endocrine therapy (<6 months or ≥ 6 months from discontinuation of adjuvant anti-estrogen therapy (e.g. tamoxifen or raloxifene) or no prior adjuvant antiestrogen therapy). Study therapy was administered daily until disease progression (objective or symptomatic) or withdrawal from therapy (e.g., due to unacceptable toxicity, withdrawal of consent, or other reason). All subjects were to be followed for survival information until death. On 13 Apr 2015, after the introduction of the Long Term Follow UP (LTFU) phase (per protocol amendment 07), subjects receiving study treatment with lapatinib plus letrozole, or letrozole plus placebo had continued access to this study treatment until the occurrence of one of the following criteria: Disease progression (as determined by the Investigator), Intercurrent illness that prevented further administration of study treatment Drug related AE which was considered by the investigator to warrant permanent discontinuation of study treatment The subject decided to withdraw from the study. Investigators collected AEs and/or SAEs related to study participation, until 30 days following study treatment discontinuation. Subjects who were being followed-up for OS but were not taking study medication, were withdrawn from the study. The study was terminated on 22-Mar-2018 (last subject last visit).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Study Comparing GW572016 and Letrozole Versus Letrozole in Subjects With Estrogen/Progesterone Receptor- Positive Advanced or Metastatic Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Lapatinib
* Drug: Letrozole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria Signed informed consent; Subjects with histologically confirmed invasive breast cancer with stage IV disease at primary diagnosis or at relapse after curative-intent surgery; Subjects with either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST). If the disease was restricted to a solitary lesion, its neoplastic nature was confirmed by cytology or histology. Tumors that were ER+ and/or PgR+; Post-menopausal female subjects ≥ 18 years of age. ECOG Performance Status of 0 or 1; Subjects who had archived tumor tissue available to compare tumor response with intra-tumoral expression of ErbB1 and ErbB2. Adjuvant therapy with an aromatase inhibitor and / or trastuzumab was allowed; however, treatment was to stop more than 1 year prior (>12 months) to the first dose of randomized therapy. Subjects must have ended hormonal replacement therapy (HRT) at least 1 month (30 days) prior to receiving the first dose of randomized therapy. Key exclusion criteria: Pre-menopausal, pregnant, or lactating; Received prior chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for advanced or metastatic disease; Bisphosphonate therapy for bone metastases was allowed; however, treatment was to be initiated prior to the first dose of randomized therapy. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, was not permitted; Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of randomized therapy (lapatinib or placebo); Subjects with known history of/clinical evidence of CNS metastases or leptomeningeal carcinomatosis; and / or subjects on concurrent anti-cancer therapies other than letrozole; and / or who have not recovered from toxicities related to prior adjuvant therapy (surgery, radiotherapy, chemotherapy etc.) Subjects with active or uncontrolled infection and/ or with history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + Letrozole 2.5 mg<br>Letrozole (2.5 mg once daily orally) with Placebo (which matched with Lapatinib tablet) | Drug: Letrozole<br>* 2.5 mg orally once a day<br>Drug: Placebo<br>* Placebo (which matched with lapatinib tablet)<br>|
| Experimental: Lapatinib 1500 mg + Letrozole 2.5 mg<br>Lapatinib (1500 mg once daily orally) with Letrozole (2.5 mg once daily orally) | Drug: Lapatinib<br>* 1500 mg orally once a day<br>* Other names: GW572016;Drug: Letrozole<br>* 2.5 mg orally once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression Free Survival (PFS) in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced or Metastatic Breast Cancer as Assessed by the Investigator | PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. The date of documented PD is defined as the date of radiological PD as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per Response Evaluation Criteria in Solid Tumors (RECIST 1.0), PD is defined as a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions. | From the date of randomization until the date of the first documented progression or date of death from any cause, whichever came first, assessed for up to 46 months | 
| Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator | PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator | PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months | 
| PFS in Participants in the ITT Population as Assessed by the Investigator | PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months | 
| Overall Survival in the HER2-Positive Population | Overall survival was defined as the time from randomization until death due to any cause. | From date of randomization until date of death due to any cause, assessed up to 46 months | 
| Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator | OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 * (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. | Up to 46 months | 
| Number of Participants With Overall Tumor Response (OR) by Stratification Factors With Measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator | Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval [DI] =>6 months or DI <6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT to the randomization date. | Up to 46 months | 
| Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator | CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement. | Up to 46 months | 
| Number of Participants With the Indicated Best Response From the Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator. | CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions. | Up to 46 months | 
| Number of Participants With the Indicated Best Response From the Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator. | CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions. | Up to 46 months | 
| Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator | Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans. | Up to 46 months | 
| Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator | Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans. | Up to 46 months | 
| Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population | The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another. | Up to 46 months | 
| Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator | TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator. | Up to 46 months | 
| Overall Survival in the ITT Population | Overall survival was defined as the time from randomization until death due to any cause. | From date of randomization until date of death due to any cause, assessed up to 46 months | 
| Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator | OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 * (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. | Up to 46 months | 
| Number of Participants With Overall Tumor Response (OR) by Stratification Factors With Measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator | Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval [DI] =>6 months or DI <6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT and the randomization date. | Up to 46 months | 
| Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator | CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement. | Up to 46 months | 
| Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator | Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans. | Up to 46 months | 
| Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator | Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans. | Up to 46 months | 
| Number of Participants With Evidence of Brain Metastases From the ITT Population | The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another. | Up to 46 months | 
| TTP for Participants From the ITT Population as Assessed by the Investigator | TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator. | Up to 46 months | 
| Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Quality of Life (QOL) was assessed using the FACT-B questionnaire, which was a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales (each ranging from 0 [not at all] to 4 [very much]) indicate a higher QOL. The score is transformed for FACT-B and results in a total score ranging from 0 to 144. Complete: completing at least 1 question from FACT-B. | Day 1 (baseline) visit; Week 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192 visits; conclusion/withdrawal visit | 
| Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Quality of Life (QOL) was assessed using the FACT-B questionnaire, which is a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales indicate a higher QOL; each ranging from 0 (not at all) to 4 (very much). The score is transformed for FACT-B and results in a total score ranging from 0 to 144. The FACT-B is designed to measure multidimensional QOL in participants with breast cancer. | Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit | 
| Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data | FACT-G is a subscale of the FACT-B QOL questionnaire and consists of 27 questions grouped into 4 domains that measure a participant's physical, functional, social and family, and emotional well-being. FACT-G is assessed on a five-point Likert-type scale, with scores ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). The total score is calculated as the sum of the item scores on the subscale; the total ranges from 0 to 108, with higher score indicating a better quality of life. | Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit | 
| Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | The TOI score is the sum of the physical well-being, functional well-being, and breast cancer unweighted subscale scores. The total TOI score ranges from 0 to 92, with higher scores representing a better quality of life. | Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit | 
| Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores | A minimally important difference (MID) is the smallest difference in a score for a measure of QOL that corresponds to a difference in function or clinical course. Responders are defined as participants with an MID => 8 for the FACT-B score, and an MID =>6 for the FACT-G and TOI scores. | Up to 46 months | 
| Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | Clinical benefit: participants with CR, PR, or SD for =>6-month period. FISH testing measures the amount of the HER2 gene in each cell. This gene is responsible for the overproduction of the HER2 protein. FISH-positive: excessive amounts of the gene are present; FISH-negative: normal levels of the gene are present. | Up to 46 months | 
| Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC is a commonly used test to assess the amount of the HER2 receptor protein on the surface of the cancer cells. The IHC test results in a score of 0 to 3+, which indicates the amount of HER2 receptor protein on the cells in a sample of breast cancer tissue. Tissue scores of 0 to 1+ indicate HER2 negativity; scores of 2+ and 3+ indicate HER2 positivity. Clinical benefit is defined as participants with CR, PR, or SD for =>6-month period. | Up to 46 months | 
| Number of Participants With Response in Participants With Baseline Serum HER2 Extracellular Domain (ECD) Baseline Values Greater Than 15 Nanograms Per Milliliter (ng/mL) and 15 ng/mL or Lower | The HER2 ECD is a glycoprotein that can be shed from the cell surface into the blood of normal individuals and can be elevated in different pathologic conditions. The serum HER2 ECD level generally reflects the tissue HER2 status. The HER2 ECD is quantified in serum with an enzyme-linked immunosorbent assay (ELISA). Non-Evaluable (NE): any participant who could not be classified as CR, PR, SD, or PD. | Up to 46 months | 
| Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Participants who had a HER2-negative tumor status based on baseline tissue with baseline serum HER2 ECD values =<15 ng/mL but later had at least two consecutive serum HER2 ECD values >15 ng/mL experienced seroconversion. | Up to 46 months | 
| Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive | Time to seroconversion was defined as the time from the date of randomization until the first instance of serum HER2 (>15 ng/mL) on two consecutive occasions. | Up to 46 months | 
| Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR is a cell surface receptor tyrosine kinase expressed in certain types of tumors. Depending upon the staining intensity, EGFR was graded as follows: 0=absence of membrane staining above background in all tumor cells; EGFR-positive=staining is defined as any IHC staining of tumor cell membranes above background level, whether it is complete or incomplete circumferential staining (1+, 2+, 3+). | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lapatinib, Letrozole, breast carcinoma, breast cancer, breast lump, HER2 positive metastatic breast cancer, breast cancer positive for human epidermal growth factor receptor 2, HER2, breast cancer progression, estrogen-receptor positive breast cancer, ER