LUX-Breast 2; Afatinib in HER2 (Human Epidermal Growth Factor Receptor)-Treatment Failures

Study Overview
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Brief Summary
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The general aim of this study is to investigate the efficacy and safety of afatinib (BIBW 2992) alone and in combination with weekly paclitaxel or weekly vinorelbine (in patients who progress on afatinib monotherapy within this trial) as treatment in patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-targeted treatment in the neoadjuvant or adjuvant setting

Official Title
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LUX-Breast 2; An Open Label, Phase II Trial of Afatinib (BIBW 2992) in Patients With Metastatic HER2-overexpressing Breast Cancer Failing HER2-targeted Treatment in the Neoadjuvant and/or Adjuvant Treatment Setting

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Vinorelbine 25 mg/m2 weekly
* Drug: Afatinib 40mg once daily (OD)
* Drug: Paclitaxel 80 mg/m2 weekly


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Female patients >=18 years with proven diagnosis of HER2-overexpressing, histologically confirmed breast cancer Stage IV metastatic disease At least one measurable lesion according to RECIST 1.1 (Response Evaluation Criteria for Solid Tumours version 1.1). Skin, bone and brain lesions are considered non-target lesions Must have failed or progressed on either trastuzumab or lapatinib or trastuzumab and lapatinib treatment in the neoadjuvant and/or adjuvant setting Exclusion criteria: Prior first line therapy for metastatic breast cancer Known pre-existing interstitial lung disease Active brain metastases History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to trial treatment. Cardiac left ventricular function with resting ejection fraction of less than 50%. Prior treatment with Epidermal Growth Factor Receptor (EGFR)/HER2-targeted small molecules or antibodies other than trastuzumab and lapatinib in the neoadjuvant or adjuvant setting Prior treatment with paclitaxel in the past 12 months Must not have received prior vinorelbine treatment - Further exclusion criteria apply

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afatinib 40mg once daily (OD)<br>Patient to receive afatinib monotherapy at a dose of 40 mg/d until progression of their disease | Drug: Afatinib 40mg once daily (OD)<br>* Patient to receive afatinib monotherapy at a dose of 40 mg/d until progression of their disease<br>|
| Experimental: Paclitaxel 80 mg/m2 weekly<br>Patients to additionally receive paclitaxel at a dose of 80 mg/m2 weekly on disease progression on afatinib monotherapy | Drug: Paclitaxel 80 mg/m2 weekly<br>* Patients to additionally receive paclitaxel at a dose of 80 mg/m2 weekly on disease progression on afatinib monotherapy<br>|
| Experimental: Vinorelbine 25 mg/m2 weekly<br>Patients to additionally receive vinorelbine at a dose of 25 mg/m2 weekly on disease progression on afatinib monotherapy | Drug: Vinorelbine 25 mg/m2 weekly<br>* Patients to additionally receive vinorelbine at a dose of 25 mg/m2 weekly on disease progression on afatinib monotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response (OR) Assessed by Response Evaluation Criteria in Solid Tumours Version (RECIST) 1.1 | Objective response according to RECIST v1.1. Best overall response of confirmed complete response (CR) or confirmed partial response (PR) recorded since first administration of trial medication and until the earliest of disease progression, death or start of next treatment in each part separately. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. Percentage of participants with OR along with exact 95% Confidence Interval by Clopper and Pearson is presented. | From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response According to RECIST v1.1 (With Confirmation) | Best overall response was assessed according to RECIST version 1.1 and was calculated relative to the baseline of each respective part .Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. | From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days | 
| Best Overall Response According to RECIST v1.1 (Regardless of Confirmation) | Best overall response was assessed according to RECIST version 1.1 and was calculated relative to the baseline of each respective part (without clinical disease assessment) .Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. | From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days | 
| Progression Free Survival (PFS) | Progression Free Survival is defined as the time from the drug start date to the date of 1st disease progression or death for monotherapy and 2nd disease progression or death from the drug start date of the combination therapy for combination therapy'. Median is calculated from the Kaplan-Meier curve. | From drug start date in monotherapy to 1st disease progression and drug start date in combination therapy to 2nd disease progression | 
| Duration of Objective Response According to RECIST v1.1 | Duration of objective response, defined as the time from first objective response to the time of progression or death. (regardless of confirmation). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. | From the first objective response to the time of progression or death, up to 1562 days | 
| Percentage of Patients With Highest Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade of 3 or Higher | Percentage of patients with highest common terminology criteria for adverse events (CTCAE) version 3.0 Grade of 3 or higher. | From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days | 
| Change From Baseline to End of Treatment in Systolic Blood Pressure (SBP) | Change from baseline to end of treatment in systolic blood pressure (SBP). | Baseline and End of treatment period, up to 1562 days | 
| Change From Baseline to End of Treatment in Diastolic Blood Pressure (DBP) | Change from baseline to end of treatment in diastolic blood pressure (DBP). | Baseline and End of treatment period, up to 1562 days | 
| Number of Patient With Possibly Clinically Significant (PCS) Laboratory Values | Number of patient with possibly clinically significant (PCS) laboratory values by functional group (haematology, differentials, coagulation, electrolytes, enzymes, and substrates). Acronyms Used: Prothrombin time-International normalized ratio (PT-INR), Alanine aminotransferase/Glutamic pyruvic transaminase (ALT/GPT) Serum glutamic pyruvic transaminase (SGPT), Aspartate aminotransferase/Glutamic-oxaloacetic transaminase (AST/GOT) Serum glutamic-oxaloacetic transaminase (SGOT) | From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days |