A Study of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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Study of trastuzumab emtansine (T-DM1) administered to patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

Official Title
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A Phase II, Single-Arm, Open-Label Study of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab emtansine [Kadcyla]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed study-specific Informed Consent Form(s) Age ≥ 18 years Histologically documented breast cancer HER2-positive disease Metastatic breast cancer Disease progression on the last chemotherapy regimen received in the metastatic setting Prior treatment with an anthracycline, trastuzumab, a taxane, lapatinib, and capecitabine in the neoadjuvant, adjuvant, locally advanced, or metastatic setting and prior treatment with at least two lines of therapy (a line of therapy can be a combination of two agents or single-agent chemotherapy) in the metastatic setting At least two lines of anti-HER2 therapy must have been given in the metastatic setting as monotherapy or combined with chemotherapy or hormonal therapy. The HER2-targeted agent can include trastuzumab, lapatinib, or an investigational agent with HER2-inhibitory activity. A minimum of 6 weeks of trastuzumab for the treatment of metastatic disease is required Patients must have had at least 14 days of exposure in the metastatic setting to lapatinib and capecitabine (given together or separately) unless they were intolerant of lapatinib and/or capecitabine Exclusion Criteria: Chemotherapy ≤ 21 days before enrollment Trastuzumab ≤ 21 days before enrollment Hormone therapy ≤ 7 days before enrollment Granulocyte-stimulating agent < 14 days before enrollment Investigational therapy ≤ 28 days before enrollment Previous radiotherapy for treatment of metastatic breast cancer ≤ 21 days before enrollment Brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastases within 3 months of the first study treatment History of intolerance (including Grade 3-4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin > 500 mg/m^2; Epirubicin > 900 mg/m^2; Mitoxantrone > 120 mg/m^2 and idarubicin > 90 mg/m^2 Peripheral neuropathy of Grade ≥ 3 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v3.0 History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma Current unstable angina History of symptomatic congestive heart failure (CHF), or ventricular arrhythmia requiring treatment History of myocardial infarction within 6 months of enrollment Left ventricular ejection fraction (LVEF) < 50% within 28 days of enrollment History of decreased LVEF to < 50% or symptomatic CHF with previous adjuvant trastuzumab treatment Severe dyspnea at rest due to complications of advanced malignancy or requiring current continuous oxygen therapy Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during the course of study treatment Current pregnancy or lactation Current known infection with human immunodeficiency virus (HIV), active hepatitis B, and/or hepatitis C virus Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab emtansine<br>Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination. | Drug: Trastuzumab emtansine [Kadcyla]<br>* Intravenous repeating dose<br>* Other names: T-DM1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Objective Response as Assessed Through Independent Radiologic Review | Objective response was defined as a complete response (CR) or partial response (PR) determined on two consecutive occasions ≥ 4 weeks apart, assessed using Response Evaluation Criteria in Solid Tumors (RECIST). CR: the disappearance of all target lesions and all nontarget lesions and normalization of tumor marker level and no new lesions. PR: disappearance of all target lesions and persistence of ≥ 1 nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, and no new lesions or unequivocal progression of existing nontarget lesions. The primary data cut-off date was 17 September 2009 (approximately 6 months after the last patient was enrolled). The final efficacy analysis was performed using a data cut-off date of 1 January 2010 (approximately 9 months after the last patient was enrolled). | From randomization until the primary analysis data cut-off date of September 2009 (6 months after last patient enrolled) and until the final efficacy analysis cut-off date of 1 January 2010 (approximately 9 months after the last patient enrolled). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Objective Response as Assessed Through Independent Radiologic Review | For participants who achieved an objective response, duration of objective response was defined as the time from the first tumor assessment that supported a participant's objective response to the time of disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Response was assessed by the independent review facility. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. For participants who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate the duration of objective response. | From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled. | 
| Progression-free Survival as Assessed Through Independent Radiologic Review | Progression-Free Survival (PFS) was defined as the time from the first day of study treatment to documented disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. Disease progression was assessed by the independent review facility. For patients who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate PFS. | From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled. | 
| Percentage of Participants With Clinical Benefit Based on Independent Radiologic Review | Clinical benefit was defined as participants who achieved an objective response (confirmed complete or partial response) between randomization and 1 January 2010, or with stable disease at 6 months. Stable disease at 6 months was defined as participants who achieved at least stable disease based on tumor assessments by the independent review facility, and remained alive and progression-free at 6 months. Stable disease was defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started, and no new lesions and/or unequivocal progression of existing nontarget lesions. Response was assessed by the independent review facility. | From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled. | 
| Objective Response Based on Investigator Assessment | Objective response was defined as a complete response (CR) or partial response (PR) determined on two consecutive occasions ≥ 4 weeks apart, assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Response was assessed by the study Investigator. CR: the disappearance of all target lesions and all nontarget lesions and normalization of tumor marker level and no new lesions. PR: disappearance of all target lesions and persistence of ≥ 1 nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, and no new lesions or unequivocal progression of existing nontarget lesions. | From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled. | 
| Progression-free Survival Based on Investigator Assessment | Progression-Free Survival (PFS) was defined as the time from the first day of study treatment to documented disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. For patients who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate PFS. | From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled. | 
| Duration of Objective Response Based on Investigator Assessment | For participants who achieved an objective response, duration of objective response was defined as the time from the first tumor assessment that supported a participant's objective response to the time of disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Response was determined by the Investigator's assessment. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. For participants who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate the duration of objective response. | From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled. | 
| Percentage of Participants With Clinical Benefit Based on Investigator Assessment | Clinical benefit was defined as participants with an objective response (confirmed complete or partial response) or stable disease at 6 months. Patients with stable disease at 6 months were defined as patients who achieved at least stable disease based on tumor assessments and remained alive and progression free at 6 months. Response was based on the Investigator's assessment. | From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, HER2-positive breast cancer, MBC, Trastuzumab emtansine