Metastatic Breast Cancer
Conditions
Keywords
MBC, Breast Cancer, HER2+, HER2+ breast cancer, HER2 positive breast cancer, herceptin, Trastuzumab emtansine
Brief summary
This was a multi-institutional, multinational, open-label, single-arm Phase Ib/II study designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of trastuzumab emtansine (trastuzumab-MCC-DM1) administered by intravenous (IV) infusion in combination with pertuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive locally advanced or metastatic breast cancer who had previously received trastuzumab.
Detailed description
There were 2 phases in the study, a Dose Escalation phase (Phase 1b) and a Dose Expansion phase (Phase 2a). In the Dose Escalation phase, 3 patients were enrolled at the first dose level (3.0 mg/kg trastuzumab emtansine) and and 6 patients were enrolled at the second dose level (3.6 mg/kg trastuzumab emtansine). An additional 58 patients were enrolled at the 3.6 mg/kg trastuzumab emtansine dose level in the Dose Expansion phase (Phase 2a) of the study.
Interventions
DRUGTrastuzumab emtansine [Kadcyla] 3.0 mg/kg
Trastuzumab emtansine was provided as a single-use lyophilized formulation.
DRUGTrastuzumab emtansine [Kadcyla] 3.6 mg/kg
Trastuzumab emtansine was provided as a single-use lyophilized formulation.
DRUGPertuzumab 420 mg
Pertuzumab was provided as a single-use formulation.
Sponsors
Roche Pharma AG
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically documented human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer. * Tumor tissue blocks or 15-20 unstained tissue slides for confirmatory central laboratory HER2 status testing and other exploratory assessments. * Prior trastuzumab in any line of therapy. * No prior trastuzumab emtansine (T-DM1) or pertuzumab therapy. * Measurable disease. * For women of childbearing potential, agreement to use an effective form of contraception and to continue its use for the duration of the study. * Life expectancy ≥ 90 days.
Exclusion criteria
* Less than 21 days since the last anti-tumor therapy, including chemotherapy, biologic, experimental, immune, hormonal, or radiotherapy for the treatment of breast cancer, with the following exceptions: Hormone-replacement therapy or oral contraceptives; palliative radiation therapy involving ≤ 25% of marrow-bearing bone if administered ≥ 14 days prior to first study treatment. * History of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab that resulted in trastuzumab being permanently discontinued. * Peripheral neuropathy of Grade ≥ 2. * History of clinically significant cardiac dysfunction. * Current severe, uncontrolled systemic disease, eg, clinically significant cardiovascular, pulmonary, or metabolic disease. * Brain metastases that are untreated, progressive, or have required any type of therapy to control symptoms from brain metastases within 60 days of the first study treatment. * History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or other malignancy with a similar expected curative outcome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline through the end of the study (up to 2 years 3 months) | A patient had an objective response if they had a complete response or a partial response on 2 consecutive occasions ≥ 4 weeks apart. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline through the end of the study (up to 2 years 3 months) | Duration of objective response was defined as the time from initial response to disease progression (PD) or death from any cause. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions. |
| Progression-free Survival Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline through the end of the study (up to 2 years 3 months) | Progression-free survival was defined as the time from randomization to first documented disease progression (PD) or death due to any cause within 30 days of the last treatment, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions. |
Countries
Belgium, Canada, France, Germany, Italy, Spain, United States
Participant flow
Recruitment details
There were 2 phases in the study, a Dose Escalation phase (Phase 1b) and a Dose Expansion phase (Phase 2a).
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle. | 3 |
| Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle. | 64 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Dose Escalation Phase - 3.0 mg/kg | Disease Progression | 1 | 0 |
| Dose Escalation Phase - 3.0 mg/kg | Patient/Legal Guardian Decision | 1 | 0 |
| Dose Escalation Phase - 3.0 mg/kg | Physician Decision | 1 | 0 |
| Dose Escalation Phase - 3.6 mg/kg | Disease Progression | 0 | 6 |
| Dose Expansion Phase - 3.6 mg/kg | Death | 0 | 1 |
| Dose Expansion Phase - 3.6 mg/kg | Disease Progression | 0 | 37 |
| Dose Expansion Phase - 3.6 mg/kg | Patient/legal Guardian Decision | 0 | 3 |
| Dose Expansion Phase - 3.6 mg/kg | Physician Decision | 0 | 3 |
| Dose Expansion Phase - 3.6 mg/kg | Started Non-protocol Anti-Cancer Therapy | 0 | 3 |
Baseline characteristics
| Characteristic | Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg | Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg | Total |
|---|---|---|---|
| Age, Continuous | 53.3 years STANDARD_DEVIATION 1.5 | 52.7 years STANDARD_DEVIATION 10.8 | 52.7 years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 3 Participants | 63 Participants | 66 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 64 / 64 |
| serious Total, serious adverse events | 0 / 3 | 22 / 64 |
Outcome results
Primary
Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
A patient had an objective response if they had a complete response or a partial response on 2 consecutive occasions ≥ 4 weeks apart. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.
Time frame: Baseline through the end of the study (up to 2 years 3 months)
Population: Treated population: All enrolled patients who had baseline measureable disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg | Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 66.7 Percentage of patients |
| Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg | Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 40.6 Percentage of patients |
Secondary
Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
Duration of objective response was defined as the time from initial response to disease progression (PD) or death from any cause. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.
Time frame: Baseline through the end of the study (up to 2 years 3 months)
Population: Treated population: All enrolled patients who had baseline measureable disease. Only patients with an objective response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg | Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 8.6 Months |
| Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg | Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 13.9 Months |
Secondary
Progression-free Survival Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
Progression-free survival was defined as the time from randomization to first documented disease progression (PD) or death due to any cause within 30 days of the last treatment, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.
Time frame: Baseline through the end of the study (up to 2 years 3 months)
Population: Treated population: All enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg | Progression-free Survival Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 13.8 Months |
| Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg | Progression-free Survival Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 6.6 Months |