A Study of Trastuzumab Emtansine (T-DM1) Sequentially With Anthracycline-based Chemotherapy, as Adjuvant or Neoadjuvant Therapy for Patients With Early Stage Herceptin (HER)2-positive Breast Cancer

Study Overview
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Brief Summary
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This single-arm open-label study assessed the safety, feasibility, and efficacy of trastuzumab emtansine (T-DM1) after the completion of anthracycline-based adjuvant/neoadjuvant chemotherapy in patients with early HER2-positive breast cancer. Patients received T-DM1 3.6 mg/kg intravenously on Day 1 of each 3-week cycle, for up to 17 cycles.

Official Title
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A Multicenter, Multinational Phase II Study to Assess the Clinical Safety and Feasibility of Trastuzumab Emtansine Sequentially With Anthracycline-based Chemotherapy, as Adjuvant or Neoadjuvant Therapy for Patients With Early Stage HER2-positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab emtansine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients ≥ 18 years of age. Locally advanced, inflammatory, or early stage, unilateral, and histologically confirmed invasive breast cancer documented at a local laboratory (patients with inflammatory breast cancer must be able to have a core needle biopsy). Herceptin (HER)2-positive tumor, confirmed by central testing using immunohistochemistry (IHC) and in situ hybridization (ISH) methods. Willingness to receive anthracycline-based chemotherapy or have received doxorubicin/cyclophosphamide (AC) OR 5-fluorouracil (FU)/epirubicin/ cyclophosphamide (FEC) in a similar dose and schedule as described in the protocol as part of neoadjuvant or adjuvant treatment. 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 should use condoms for the duration of the study. Specific country requirements will be followed. Negative results of serum pregnancy test for premenopausal women of reproductive capacity and for women < 12 months after menopause. Patients may enroll before or after AC/FEC chemotherapy has completed. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate hematologic, biochemistry, and cardiac assessments. Exclusion Criteria: Stage IV breast cancer or bilateral breast cancer. Pregnant or breastfeeding women. History of other malignancy within the previous 5 years, except contralateral breast cancer and ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS), appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with outcome similar to those mentioned above. Radiation therapy, immunotherapy, or biotherapy within 5 years before study enrollment; non-cardiotoxic chemotherapy for malignancy treated > 5 years before study enrollment is allowed. Patients receiving AC/FEC in a similar fashion to the study treatment prescribed for adjuvant or neoadjuvant treatment of breast cancer will be allowed to enroll in the study after the completion of their AC/FEC. No other prior history of cardiotoxic chemotherapy is allowed. Active cardiac history. Current chronic daily treatment with oral corticosteroids or equivalent. Patients with severe dyspnea at rest or requiring supplementary oxygen therapy. Active, unresolved infections at screening. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Major surgery within 4 weeks before enrollment that is unrelated to the breast cancer. Patients for whom concomitant radiotherapy + T-DM1 may be contraindicated yet radiation therapy is planned. Known hypersensitivity to any of the study drugs or derivatives, including murine proteins. Grade ≥ 2 peripheral neuropathy at Baseline.

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 3.6 mg/kg was administered intravenously on Day 1 of each 3-week treatment cycle up to a maximum of 17 cycles. | Drug: Trastuzumab emtansine<br>* Trastuzumab emtansine was provided as a single-use lyophilized formulation in a glass vial.<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 a Cardiac Event Within 12 Weeks After the Start of Trastuzumab Emtansine Treatment | A cardiac event was defined as death from a cardiac cause or severe congestive failure (New York Heart Association [NYHA] Class III or IV) with a decrease in left ventricular ejection fraction (LVEF) of ≥ 10% from Baseline to an LVEF of < 50%. | Baseline to 12 weeks after the start of trastuzumab emtansine treatment | 
| Adverse Events, LVEF Function, and Deaths | The following percentages of participants are reported: At least 1 adverse event while receiving T-DM1; at least 1 serious adverse event while receiving T-DM1; an adverse event leading to discontinuation, dose delay, or dose reduction of trastuzumab emtansine treatment; symptomatic cardiac dysfunction; and asymptomatic decline in left ventricular ejection fraction (LVEF). An asymptomatic LVEF decline was defined as a LVEF < 50% and a maximum decrease ≥ 10% from Baseline. The percentage of participants who died is reported. | From the start to the end of trastuzumab emtansine treatment (up to 51 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced at Least 1 Adverse Event During Concurrent Radiotherapy With Trastuzumab Emtansine Treatment |  | From the start to the end of concurrent radiotherapy (up to 51 weeks) | 
| Percentage of Participants Who Experienced at Least 1 Adverse Event During Concurrent Hormonal Therapy With Trastuzumab Emtansine Treatment |  | From the start to the end of concurrent hormonal therapy (up to 51 weeks) | 
| Percentage of Participants Who Completed the Planned Duration of Trastuzumab Emtansine Treatment | Participants were to receive up to a total of 17 cycles of trastuzumab emtansine. If trastuzumab was given concurrently with either the optional docetaxel or optional radiation, then the number of 3-week cycles of trastuzumab therapy was subtracted from the planned 17 cycles of trastuzumab emtansine therapy. | From the start to the end of trastuzumab emtansine treatment (up to 51 weeks) | 
| Percentage of Participants Who Completed ≥ 95% of the Planned Radiotherapy Treatment With Concurrent Trastuzumab Emtansine Administration Without Significant (> 5 Days) Delay |  | From the start to the end of radiotherapy treatment (up to 51 weeks) | 
| Percentage of Participants With a Pathological Complete Response | Pathological complete response was defined as the absence of invasive neoplastic cells at microscopic examination of the primary tumor and lymph nodes after surgery following primary systemic therapy. Pathological complete response was evaluated in participants treated with neoadjuvant therapy doxorubicin/cyclophosphamide-5-fluorouracil/epirubicin/cyclophosphamide followed by 1 or more doses of trastuzumab emtansine and who underwent surgery. | Day of surgery | 
| Disease-free Survival at Month 12 | Disease-free survival was defined as the time from date of first protocol treatment for adjuvant patients or date of surgery for neoadjuvant patients to disease recurrence, occurrence of invasive contralateral breast cancer, other second primary cancer (excluding non-breast second primary), or death, whichever occurred first. | From the start of trastuzumab emtansine for adjuvant patients and from the date of surgery for neoadjuvant patients to 12 months later |