A Randomized, Multicenter, Phase III Open-label Study of the Efficacy and Safety of Trastuzumab MCC-DM1 vs. Capecitabine + Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-Based Therapy
Overview
- Phase
- Phase 3
- Intervention
- Trastuzumab emtansine
- Conditions
- Breast Cancer
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 991
- Primary Endpoint
- Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC)
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief 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 in participants with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer. Participants will be treated until disease progression (PD), unmanageable toxicity, or study termination. Once disease progression is reported, all participants will be followed for survival every 3 months until death, loss to follow-up, withdrawal of consent, or study termination.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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 (which occur during or after most recent treatment or within 6 months after completing of adjuvant therapy) of incurable, unresectable, locally advanced or metastatic breast cancer, defined by the investigator
- •Measurable and/or nonmeasurable disease; participants with central nervous system-only disease are excluded
- •Cardiac ejection fraction greater than or equal to (\>/=) 50 percent (%) by either echocardiogram or multi-gated acquisition 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
- •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 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
Arms & Interventions
Trastuzumab emtansine
Participants will receive trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (IV) infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until disease progression (PD) (as assessed by the investigator), unmanageable toxicity, or study termination.
Intervention: Trastuzumab emtansine
Lapatinib + Capecitabine
Participants will receive lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 milligrams per square meter (mg/m\^2) orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Eligible participants will cross over to receive trastuzumab emtansine if second interim analysis demonstrates statistically significant overall survival benefit in favor of trastuzumab emtansine.
Intervention: Lapatinib
Lapatinib + Capecitabine
Participants will receive lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 milligrams per square meter (mg/m\^2) orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Eligible participants will cross over to receive trastuzumab emtansine if second interim analysis demonstrates statistically significant overall survival benefit in favor of trastuzumab emtansine.
Intervention: Capecitabine
Outcomes
Primary Outcomes
Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC)
Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)
PD was assessed by an IRC using modified Response Evaluation Criteria in Solid Tumors (RECIST). All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as target lesions (TLs) and recorded 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 was calculated as 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 greater than or equal to (\>/=) 20 percent (%) increase in SLD, taking as reference smallest SLD recorded since treatment started or appearance of 1 or more new lesions. PD for non-TLs was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Percentage of Participants with PD by IRC or death from any cause was reported.
Progression-free Survival (PFS) as Assessed by an IRC (Co-primary Endpoint)
Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months)
Tumor response was assessed by an IRC according to modified RECIST. All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as TLs (on the basis of their size and their suitability for accurate repeated measurements either by imaging or clinically) and recorded at baseline. A sum of the longest diameter for all TLs was calculated as baseline SLD. All other lesions were identified as non-TLs and recorded at baseline. PD for TLs: \>/= 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or appearance of 1 or more new lesions. PD for non-TLs: appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. PFS: time from randomization to first documented PD by IRC or death from any cause (whichever occurred earlier). The median duration of PFS was estimated using Kaplan-Meier method. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley.
Percentage of Participants Who Died: Second Interim Analysis
Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months)
The percentage of participants who died from any cause was reported. The results are reported from second interim analysis, which deemed to be the confirmatory.
Overall Survival: Second Interim Analysis (Co-primary Endpoint)
Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months)
OS was defined as the time from the date of randomization to the date of death from any cause. The median duration of OS was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley. The results are reported from second interim analysis, which deemed to be the confirmatory.
Percentage of Participants Who Died: Final Analysis
Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months)
The percentage of participants who died from any cause was reported. The results reported are from the final analysis. The final analysis is descriptive.
Overall Survival: Final Analysis
Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months)
OS was defined as the time from the date of randomization to the date of death from any cause. The median duration of OS was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley. The results reported are from the final analysis. The final analysis is descriptive.
Percentage of Participants Who Were Alive at Year 1
Time Frame: Year 1
1 year survival was defined as the percentage of participants alive 1 year after starting treatment. The results reported are from the final analysis.
Percentage of Participants Who Were Alive at Year 2
Time Frame: Year 2
2 year survival was defined as the percentage of participants alive 2 years after starting treatment. The results reported are from the final analysis.
Secondary Outcomes
- Percentage of Participants With PD or Death as Assessed by the Investigator(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- PFS as Assessed by the Investigator(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- Percentage of Participants With Objective Response (OR) as Assessed by an IRC(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- Duration of Objective Response (DOR) as Assessed by an IRC(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- Percentage of Participants With Clinical Benefit as Assessed by an IRC(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- Percentage of Participants With Treatment Failure(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- Time to Treatment Failure(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- Percentage of Participants With Symptom Progression(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))
- Time to Symptom Progression(From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months))