An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer

Breast Cancer Clinical Trial

— EMILIA  

Official title:

A Randomized, Multicenter, Phase III Open-label Study of the Efficacy and Safety of Trastuzumab Emtansine vs. Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-based Therapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00829166
• Other study ID #: BO21977
• Secondary ID: TDM4370g
• Status: Active, not recruiting
• Phase: Phase 3
• First received: January 22, 2009
• Last updated: April 2, 2015
• Start date: February 2009
• Est. completion date: June 2015

Study information

• Verified date: April 2015
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is a Phase III, randomized, multicenter, international, 2-arm, open-label clinical trial designed to compare the safety and efficacy of trastuzumab emtansine (T-DM1) with that of capecitabine + lapatinib for HER2-positive metastatic breast cancer (MBC). Patients were treated until disease progression, unmanageable toxicity, or study termination. Once disease progression was reported, all patients were followed for survival every 3 months until death, loss to follow-up, withdrawal of consent, or study termination.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 991
• Est. completion date: June 2015
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• (Human epidermal growth factor receptor 2 (HER2) status must be prospectively, centrally tested and be HER2-positive based on central laboratory assay results.

• Histologically or cytologically confirmed invasive breast cancer.

• Prior treatment for breast cancer in the adjuvant, unresectable, locally advanced, or metastatic setting must include both a taxane, alone or in combination with another agent, and trastuzumab, alone or in combination with another agent.

• Documented progression of incurable, unresectable, locally advanced or metastatic breast cancer, defined by the investigator.

• Measurable and/or nonmeasurable disease; patients with central nervous system (CNS)-only disease are excluded.

• Cardiac ejection fraction = 50% by either echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective, non-hormonal form of contraception; contraception use should continue for the duration of the study treatment and for at least 6 months after the last dose of study treatment.

Exclusion Criteria:

• History of treatment with trastuzumab emtansine (T-DM1).

• Prior treatment with lapatinib or capecitabine.

• Peripheral neuropathy of Grade = 3 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0.

• History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, synchronous or previously diagnosed HER2-positive breast cancer, or cancers with a similar curative outcome as those mentioned above.

• History of receiving any anti-cancer drug/biologic or investigational treatment within 21 days prior to randomization except hormone therapy, which could be given up to 7 days prior to randomization; recovery of treatment-related toxicity consistent with other eligibility criteria.

• History of radiation therapy within 14 days of randomization.

• Brain metastases that are untreated, symptomatic, or require therapy to control symptoms, as well as any history of radiation, surgery, or other therapy, including steroids, to control symptoms from brain metastases within 2 months (60 days) of randomization.

• History of symptomatic congestive heart failure (CHF) or serious cardiac arrhythmia requiring treatment.

• History of myocardial infarction or unstable angina within 6 months of randomization.

• Current dyspnea at rest due to complications of advanced malignancy or current requirement for continuous oxygen therapy.

• Current severe, uncontrolled systemic disease (eg, clinically significant cardiovascular, pulmonary, or metabolic disease).

• Pregnancy or lactation.

• Current known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.

• Presence of conditions that could affect gastrointestinal absorption: Malabsorption syndrome, resection of the small bowel or stomach, and ulcerative colitis.

• History of intolerance (such as Grade 3-4 infusion reaction) to trastuzumab.

• Known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase deficiency.

• Current treatment with sorivudine or its chemically related analogs, such as brivudine.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Trastuzumab emtansine [Kadcyla]
Trastuzumab emtansine was provided as a single-use lyophilized formulation.
• Lapatinib
Lapatinib was available as film-coated tablets.
• Capecitabine
Capecitabine was available as film-coated tablets.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Bosnia and Herzegovina,  Brazil,  Bulgaria,  Canada,  Colombia,  Denmark,  Finland,  France,  Germany,  Hong Kong,  India,  Italy,  Korea, Republic of,  Mexico,  New Zealand,  Philippines,  Poland,  Portugal,  Russian Federation,  Singapore,  Slovenia,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) Assessed by an Independent Review Committee	PFS was defined as the time from randomization to progressive disease (PD) or death from any cause, whichever occurred earlier. All measurable lesions up to a maximum of 5 per organ and 10 in total, representative of all involved organs, should be identified as target lesions (TL) and recorded and measured at baseline. TLs should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements either by imaging or clinically. A sum of the longest diameter for all TLs will be calculated and reported as the baseline sum longest diameter (SLD). All other lesions (or sites of disease) should be identified as non-TLs and recorded at baseline. PD for TLs was defined as = 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. PD for non-TLs was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs.	From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)	No
Primary	Overall Survival	Overall survival was defined as the time from the date of randomization to the date of death from any cause. The results reported are from an interim analysis; results from the final analysis will be reported when the study is completed.	From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months)	No
Primary	1 and 2 Year Survival	1 and 2 year survival were defined as the percentage of patients alive 1 and 2 years after starting treatment.	From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months)	No
Secondary	Progression-free Survival (PFS) Assessed by the Investigator	PFS was defined as the time from randomization to progressive disease (PD) or death from any cause, whichever occurred earlier. PD for TLs was defined as = 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. PD for non-TLs was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs.	From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)	No
Secondary	Objective Response (OR) Assessed by the Independent Review Committee	OR was defined as the percentage of patients with a complete response (CR) or partial response (PR). For TLs, a CR was defined as the disappearance of all TLs and a PR was defined as = 30% decrease in the SLD of TLs, taking as reference the baseline SLD. For non-TLs, a CR was defined as the disappearance of all non-TLs and a PR was defined as the persistence of 1 or more non-TLs.	From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)	No
Secondary	Duration of Objective Response (OR)	Duration of OR was defined as the time from first documented OR to first documented progressive disease (PD) or death from any cause, whichever occurred earlier. PD for target lesions was defined as = 20% increase in the sum of the longest diameter, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of 1 or more new lesions. PD for non-target lesions was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions.	From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)	No
Secondary	Clinical Benefit	Clinical benefit was defined as the percentage of patients with a complete response (CR), partial response (PR), or stable disease (SD) at 6 months after randomization. For target lesions a CR was defined as the disappearance of all target lesions, a PR was defined as = 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For non-target lesions, a CR was defined as the disappearance of all non-target lesions and a PR was defined as the persistence of 1 or more non-target lesions, and SD was defined as the persistence of 1 or more non-target lesion.	6 months after randomization	No
Secondary	Time to Treatment Failure	Time to treatment failure was defined as the time from randomization to discontinuation of treatment for any reason, including progressive disease (PD), treatment toxicity, or death from any cause. PD for target lesions was defined as = 20% increase in the sum of the longest diameter, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of 1 or more new lesions. PD for non-target lesions was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions.	From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)	No
Secondary	Time to Symptom Progression	Time to symptom progression was defined as the time from randomization to the first symptom progression as measured by the Functional Assessment of Cancer Therapy-for patients with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer patients (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.	From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)	No