A Study of the Efficacy and Safety of Trastuzumab Emtansine (Trastuzumab-MCC-DM1) vs. Trastuzumab (Herceptin®) and Docetaxel (Taxotere®) in Patients With Metastatic HER2-positive Breast Cancer Who Have Not Received Prior Chemotherapy for Metastatic Disease

Study Overview
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Brief Summary
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This was a Phase II, randomized, multicenter, international, 2-arm, open-label clinical trial designed to explore the efficacy and safety of trastuzumab emtansine (T-DM1) relative to the combination of trastuzumab and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced breast cancer and/or metastatic breast cancer who have not received prior chemotherapy for metastatic disease.

Official Title
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A Randomized, Multicenter, Phase ii Study of the Efficacy and Safety of Trastuzumab-MCC-DM1 vs. Trastuzumab (Herceptin®) and Docetaxel (Taxotere®) in Patients With Metastatic HER2-positive Breast Cancer Who Have Not Received Prior Chemotherapy for Metastatic Disease

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab emtansine [Kadcyla]
* Drug: Trastuzumab
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the breast with locally advanced or metastatic disease, and a candidate for chemotherapy. Human epidermal growth factor receptor 2 (HER2)-positive. No prior chemotherapy for their metastatic breast cancer (MBC). Measurable disease. Age ≥ 18 years. For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective, non-hormonal form of contraception or 2 effective forms of non-hormonal contraception by the patient and/or partner. Contraception use must continue for the duration of study treatment and for at least 6 months after the last dose of study treatment. Male patients whose partners are pregnant should use condoms for the duration of the study. Exclusion Criteria: History of any chemotherapy for MBC. An interval of < 6 months from the completion of cytotoxic chemotherapy in the neo-adjuvant or adjuvant setting until the time of metastatic diagnosis. Trastuzumab ≤ 21 days prior to randomization. Hormone therapy < 7 days prior to randomization. Current peripheral neuropathy of Grade ≥ 3. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those previously mentioned. Previous radiotherapy for the treatment of unresectable, locally advanced or metastatic breast cancer is not allowed if more than 25% of marrow-bearing bone has been irradiated or the last fraction of radiotherapy has been administered within approximately 3 weeks prior to randomization. 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 2 months prior to randomization. History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin > 500 mg/m^2; epirubicin > 900 mg/m^2; mitoxantrone > 120mg/m^2 and idarubicin > 90 mg/m^2. Current unstable angina. History of symptomatic congestive heart failure, or ventricular arrhythmia requiring treatment. History of myocardial infarction within 6 months prior to randomization. Left ventricular ejection fraction (LVEF) below 50% within approximately 28 days prior to randomization. History of decreased LVEF or symptomatic congestive heart failure (CHF) with previous adjuvant trastuzumab treatment. Cardiac troponin I ≥ 0.2 ng/mL within 28 days of randomization. Severe dyspnea at rest because of complications of advanced malignancy or requiring current continuous oxygen therapy. Current severe, uncontrolled systemic disease (eg, clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures). Major surgical procedure or significant traumatic injury within approximately 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment. Current pregnancy or lactation. History of receiving any investigational treatment within approximately 28 days prior to randomization. Current known infection with human immunodeficiency virus (HIV), active hepatitis B and/or hepatitis C virus. History of intolerance (including Grade 3-4 infusion reaction) or hypersensitivity to trastuzumab, murine proteins, or docetaxel. Known hypersensitivity to any of the study drugs, including the excipients, or any drugs formulated in polysorbate 80. 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab emtansine<br>Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) administered over 30-90 minutes every 3 weeks on Day 1 of each 21-day cycle. | Drug: Trastuzumab emtansine [Kadcyla]<br>* The total dose depended on the patient's weight on Day 1 of each cycle. Trastuzumab emtansine was administered every 3 weeks until investigator-assessed radiographic or clinical progressive disease (or until second disease progression for patients who crossed over), unacceptable toxicity, or study closure, whichever occurred first.<br>* Other names: T-DM1;|
| Active Comparator: Trastuzumab + docetaxel<br>Patients received a loading dose of trastuzumab 8 mg/kg IV + docetaxel 75 or 100 mg/m^2 IV on Day 1 of Cycle 1 followed by trastuzumab 6 mg/kg IV + docetaxel 75 or 100 mg/m^2 IV on Day 1 of all subsequent 21-day cycles. | Drug: Trastuzumab<br>* The dose of trastuzumab was recalculated if body weight changed by more than ±10% from baseline. Trastuzumab was administered every 3 weeks until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity. Patients in the trastuzumab + docetaxel arm who discontinued study treatment because of progressive disease were eligible to cross-over to trastuzumab emtansine treatment until a second progressive disease event, clinical deterioration, and/or intolerance.<br>* Other names: Herceptin;Drug: Docetaxel<br>* Docetaxel was given at a dose of 75 or 100 mg/m^2 based on the investigator's decision. Patients in the trastuzumab + docetaxel arm who discontinued study treatment because of progressive disease were eligible to cross-over to trastuzumab emtansine treatment until a second progressive disease event, clinical deterioration, and/or intolerance.<br>* Other names: Taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) by the Investigator Using Modified Response Evaluation Criteria In Solid Tumors (RECIST) | PFS was defined as the time from randomization (R) to first documented investigator-assessed radiographic or clinical disease progression (PD) or death due to any cause, whichever occurred first. For target lesions (TL), PD was defined as at least a 20% increase in the sum of the longest diameter (SLD) of TLs, taking as reference the SLD recorded since treatment started or the appearance of 1 or more new lesions. For non-TLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Data for patients without PD or death were censored at the last date of tumor assessment prior to crossover (or, if no tumor assessment was performed after Baseline, at the R date +1 day). Data for patients who were lost to follow-up were censored at the last date of tumor assessment prior to crossover at which the patient was known to be progression free. Data for patients with no post-baseline tumor assessment were censored at the R date +1 day. | Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from randomization to the date of death from any cause. Patients who were alive at the time of analysis were censored at the date on which they were last known to be alive. Patients with no post-baseline were censored at the date of randomization plus 1 day. | Baseline through the data cut-off date of 31 Aug 2011 (up to 2 years, 11 months) | 
| Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | A patient had an objective response if they had a complete response or a partial response on 2 consecutive occasions ≥ 4 weeks apart. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions. | Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months) | 
| Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | Duration of objective response was defined as the time from initial response to investigator-assessed radiographic or clinical disease progression or death on study from any cause. For target lesions, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, disease progression was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions. | Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months) | 
| Clinical Benefit (CB) Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | CB was defined as an objective response (complete response [CR], partial response [PR]) or stable disease (SD) for 6 months after randomization. For target lesions (TL), CR=the disappearance of all TL; PR=at least a 30% decrease in the sum of the longest diameter (LD) of TL, taking as reference the baseline sum LD; SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=at least a 20% increase in the sum of the LD of TL, taking as reference the smallest sum of the LD recorded since the treatment started or the appearance of 1 or more new lesions. For non-TL, CR=the disappearance of all non-TL; PR=the persistence of 1 or more non-TL; SD=the persistence of 1 or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits; PD=the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TL. | Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months) | 
| Time to Symptom Progression | Time to symptom progression was defined as the time from randomization to the first documentation of a ≥ 5-point decrease from baseline in the Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) subscale score of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. The FACT-B questionnaire is a valid and reliable measure of symptoms associated with breast cancer. The TOI-PFB is a 24-item subscale generated using 3 subsections (Physical Well-Being [7 items], Functional Well-Being [7 items], and Additional Concerns [10 items]) from the FACT-B questionnaire. Patients responded to each item on a scale of 0-4 (Not at all-Very much). The total score ranged from 0 to 96. A higher score indicates fewer symptoms. A positive change score indicates improvement. | Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months) | 
| Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine and Total Trastuzumab | Serum samples were collected from all 67 patients enrolled in the trastuzumab emtansine arm using sparse pharmacokinetic sampling. Blood samples were collected prior to dosing and 30 minutes post-infusion of trastuzumab emtansine at Cycles 1 and 5. Serum samples were assayed for trastuzumab emtansine and total trastuzumab (sum of unconjugated trastuzumab and emtansine conjugated to trastuzumab) in indirect sandwich ELISAs. The area under the concentration-time curve (AUC) was estimated based on non-compartmental analysis using WinNonlin (Version 5.2.1) software. | Baseline through Cycle 5 (up to 4 months) | 
| Plasma Concentration of Free Emtansine | Plasma samples were collected from all 67 patients in the trastuzumab emtansine group 30 minutes post-infusion of trastuzumab emtansine at Cycles 1 and 5. The plasma samples were assayed for free emtansine in a mass-spectrometric assay. | Baseline through Cycle 5 (up to 4 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive breast cancer, HER2, Herceptin, Taxotere, MBC, Breast cancer, TDM1, TDM-1, HER2-positive, HER2+, HER2 positive breast cancer, HER2+ breast cancer, Armed Herceptin, Trastuzumab emtansine, Trastuzumab DM1