A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Participants With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy

Study Overview
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Brief Summary
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This randomized, multicenter, 2-arm, open-label study (TH3RESA) will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) in comparison with treatment of the physician's choice in participants with metastatic or unresectable locally advanced/recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible participants will be randomized to receive either trastuzumab emtansine 3.6 mg/kg intravenously every 21 days or treatment of the physician's choice. Participants continue to receive study treatment until disease progression or unacceptable toxicity occurs. This study is also known under Roche study protocol number BO25734.

Official Title
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A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician's Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab emtansine
* Drug: Treatment of physician's choice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants ≥ 18 years of age. Histologically or cytologically documented breast cancer. Metastatic or unresectable locally advanced/recurrent breast cancer. HER2-positive disease by prospective laboratory confirmation. Disease progression on the last regimen received as defined by the investigator. Prior treatment with an trastuzumab, a taxane, and lapatinib. Disease progression after at least two regimens of HER2-directed therapy in the metastatic or unresectable locally advanced/recurrent setting. Adequate organ function, as evidenced by laboratory results. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram or multi gated acquisition scan. Exclusion Criteria: Chemotherapy ≤ 21 days before first study treatment. Trastuzumab ≤ 21 days before first study treatment. Lapatinib ≤ 14 days before first study treatment. Prior enrollment in a trastuzumab emtansine containing study, regardless whether the patient received prior trastuzumab emtansine. Brain metastases that are untreated or symptomatic, or require any radiation, surgery or corticosteroid therapy to control symptoms within 1 month of randomization.

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>Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity. | Drug: Trastuzumab emtansine<br>* The dose was calculated based on the patient's Baseline weight on Day 1 of each 3-week treatment cycle. The same dose was administered in subsequent cycles if the patient's weight stayed within 10% of the Baseline weight. If there was a weight change > 10%, the dose was adjusted accordingly and the recorded weight became the new Baseline weight. Trastuzumab emtansine was provided as a single-use lyophilized formulation.<br>* Other names: T-DM1;|
| Active Comparator: Treatment of physician's choice<br>Treatment of physician's choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy. | Drug: Treatment of physician's choice<br>* The treatment of physician's choice (TPC) was a protocol-specified approved or standard of care therapy or combination of therapies, based on frequently used regimens for late-line HER2-positive metastatic breast cancer treatment after receipt of both trastuzumab- and lapatinib-containing regimens. The therapies included single-agent chemotherapy, single-agent (e.g., tamoxifen or aromatase inhibitor) or dual-agent (e.g., aromatase inhibitor with luteinizing hormone releasing hormone [LHRH] agonist) hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy. Participants who had documented progressive disease (PD) were eligible to switch treatment to receive trastuzumab emtansine 3.6 mg/kg. Participants who switched treatment remained on trastuzumab emtansine treatment until another PD event or unmanageable toxicity. The formulation, storage, and preparation of all TPC were as per the appropriate package insert or national prescribing information.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was defined as the time from randomization to the first documented disease progression by investigator assessment using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death from any cause, whichever occurred first. Progression-free survival was a co-primary endpoint. | Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) | 
| Overall Survival | Overall survival (OS) was defined as the time from randomization to death from any cause. Overall survival was a co-primary endpoint. | Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Objective Response | An objective response was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders. | Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) | 
| Duration of the Objective Response | Duration of the objective response was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first. | Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) | 
| 6-month and 1-year Survival | 6-month and 1-year survival were defined as the percentage of participants who were alive at 6 months and 1 year, respectively, as estimated using Kaplan-Meier method. | Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) | 
| Time to Pain Symptom Progression | Time to pain symptom progression was defined as the time from randomization to the first documentation of an increase in narcotic use and/or a 10 point increase from Baseline in the pain score as measured by the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire for patients with bone metastases (EORTC QLQ-BM22). The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain. | Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) | 
| Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle | The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain. A negative change score indicates improvement. | Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) | 
| Overall Survival (Final Analysis) | Overall survival was defined as the time from randomization to death from any cause. | Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years) | 
| 6-month and 1-year Survival (Final Analysis) | 6-month and 1-year survival were defined as the percentage of participants who were alive at 6 months and 1 year, respectively, as estimated using Kaplan-Meier method. | Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years) |