Clinical trial NCT00679341: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: 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
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2008-05-16
Enrollment: 137
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Progression-free Survival (PFS) by the Investigator Using Modified Response Evaluation Criteria In Solid Tumors (RECIST)
timeFrame: Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months)
Secondary outcomes:
measure: Overall Survival
timeFrame: Baseline through the data cut-off date of 31 Aug 2011 (up to 2 years, 11 months)
measure: Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months)
measure: Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months)
measure: Clinical Benefit (CB) Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months)
measure: Time to Symptom Progression
timeFrame: Baseline through the data cut-off date of 15 Nov 2010 (up to 2 years, 2 months)
measure: Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine and Total Trastuzumab
timeFrame: Baseline through Cycle 5 (up to 4 months)
measure: Plasma Concentration of Free Emtansine
timeFrame: Baseline through Cycle 5 (up to 4 months)
Other outcomes:
Locations:
Study officials:
affiliation: Genentech, Inc.
name: Ellie Guardino, MD/PhD
role: STUDY_DIRECTOR
References:
citation: Perez EA, Hurvitz SA, Amler LC, Mundt KE, Ng V, Guardino E, Gianni L. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res. 2014 May 23;16(3):R50. doi: 10.1186/bcr3661.
citation: Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. doi: 10.1200/JCO.2012.44.9694. Epub 2013 Feb 4.