Breast Cancer
Conditions
Keywords
Human Epidermal Growth Factor Receptor 2 (HER2), Positive Early Breast Cancer
Brief summary
The purpose of this research study is to compare the effectiveness and safety of ABP 980 against trastuzumab in women with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.
Interventions
DRUGABP 980
ABP 980 was administered at an initial dose of 8 mg/kg over a 90-minute intravenous (IV) infusion, then 6 mg/kg IV infusion Q3W for all subsequent cycles.
DRUGTrastuzumab
Trastuzumab was administered at an initial dose of 8 mg/kg over a 90-minute IV infusion, then 6 mg/kg IV infusion Q3W for all subsequent cycles.
DRUGPaclitaxel
Paclitaxel, 175 mg/m² Q3W for 4 cycles (or 80 mg/m² QW for 12 cycles, if local standard of care).
PROCEDURELumpectomy or Mastectomy with Sentinel Node or Axillary Node Dissection
Sponsors
Actavis Inc.
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Females ≥ 18 years of age * Histologically confirmed invasive breast cancer * Planning for surgical resection of breast tumor and sentinel node or axillary lymph node resection * Planning neoadjuvant chemotherapy * HER2 positive disease * Measurable disease in the breast after diagnostic biopsy, defined as longest diameter ≥ 2.0 cm * Known estrogen receptor (ER) and progesterone receptor (PR) hormone receptor status at study entry * Normal bone marrow function * Normal hepatic function * Normal renal function * Subjects must sign an Institutional Review Board/Ethics Committee (IRB/EC)-approved informed consent form before any study specific procedures Inclusion Criteria for Randomization: * Left ventricular ejection fraction (LVEF) of ≥55% by 2D echocardiogram * Complete all 4 cycles of run-in chemotherapy
Exclusion criteria
* Bilateral breast cancer * Presence of known metastases * Received prior treatment, including chemotherapy, biologic therapy, radiation or surgery with the exception of diagnostic biopsy for primary breast cancer * Other concomitant active malignancy or history of malignancy in the past 5 years except treated basal cell carcinoma of the skin or carcinoma in situ of the cervix * Pre-existing clinically significant (≥ grade 2) peripheral neuropathy * Any history of documented or current congestive heart failure, current high-risk uncontrolled arrhythmias, current angina pectoris requiring a medicinal product, current clinically significant valvular disease, current evidence of transmural infarction on electrocardiogram (ECG), or current poorly controlled hypertension * Severe dyspnea at rest requiring supplementary oxygen therapy * History of positivity for hepatitis B surface antigen, hepatitis C virus, or human immunodeficiency virus (HIV) * Recent infection requiring a course of systemic anti-infectives that were completed ≤ 14 days before enrollment (with the exception of uncomplicated urinary tract infection) * Woman of childbearing potential who is pregnant or is breast feeding * Woman of childbearing potential who is not consenting to use highly effective methods of birth control (eg, true abstinence \[periodic abstinence (eg calendar ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception\], sterilization, or other non-hormonal forms of contraception) during treatment and for at least 7 months after the last administration of the protocol specified treatment * Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study * Other investigational procedures while participating in this study are excluded * Subject has known sensitivity to any of the products to be administered during the study, including mammalian cell derived drug products, trastuzumab, murine proteins, or to any of the excipients * Subject previously has enrolled and/or has been randomized in this study * Subject likely to not be available to complete all protocol required study visits or procedures * History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Pathologic Complete Response | 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase | Pathologic complete response (pCR) was defined as the absence of invasive tumor cells in the breast tissue and in axillary lymph nodes, regardless of residual ductal carcinoma in situ (DCIS). Participants underwent a lumpectomy or mastectomy with sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND) within 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase. The pathology evaluation of surgical specimens for pCR analysis was conducted by local laboratories at the study sites. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Pathologic Complete Response in Breast Tissue Only | 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase | Pathologic complete response (pCR) was defined as the absence of invasive tumor cells in the breast tissue, regardless of residual ductal carcinoma in situ (DCIS). Participants underwent a lumpectomy or mastectomy with sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND) within 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase. The pathology evaluation of surgical specimens for pCR analysis was conducted by local laboratories at the study sites. |
| Percentage of Participants With a Pathologic Complete Response in Breast Tissue and Axillary Lymph Nodes and Absence of DCIS | 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase | Pathological complete response was defined as the absence of invasive tumor cells in the breast tissue and axillary lymph node(s) and absence of residual DCIS. Participants underwent a lumpectomy or mastectomy with sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND) within 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase. The pathology evaluation of surgical specimens for pCR analysis was conducted by local laboratories at the study sites. |
Countries
Belarus, Brazil, Bulgaria, Canada, Chile, Germany, Greece, Hungary, Italy, Mexico, Poland, Romania, Russia, Serbia, South Africa, Spain, Ukraine, United Kingdom
Participant flow
Recruitment details
This study was conducted at 123 sites in 20 countries from April 2013 to January 2017. The study consisted of a neoadjuvant treatment phase for 4 cycles, surgery, and adjuvant treatment for up to one year from the first day of study drug administration in the neoadjuvant phase.
Pre-assignment details
Enrolled patients received run-in chemotherapy consisting of epirubicin and cyclophosphamide every 3 weeks for 4 cycles. After the run-in, participants with adequate cardiac function were randomized. Randomization was stratified by tumor stage, nodal status, hormone receptor status, planned paclitaxel dosing schedule, and geographic region.
Participants by arm
| Arm | Count |
|---|---|
| ABP 980 Participants received ABP 980 at an initial dose of 8 mg/kg over a 90-minute intravenous (IV) infusion, then 6 mg/kg IV infusion every 3 weeks (Q3W) for 3 additional cycles plus 175 mg/m² paclitaxel Q3W for 4 cycles. | 364 |
| Trastuzumab Participants received trastuzumab at an initial dose of 8 mg/kg over a 90-minute IV infusion, then 6 mg/kg IV infusion Q3W for 3 additional cycles plus 175 mg/m² paclitaxel Q3W for 4 cycles. | 361 |
| Total | 725 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Adjuvant Phase | Death | 0 | 0 | 0 | 0 | 3 |
| Adjuvant Phase | Disease Progression or Recurrence | 0 | 0 | 12 | 4 | 3 |
| Adjuvant Phase | Other | 0 | 0 | 1 | 0 | 0 |
| Adjuvant Phase | Physician Decision | 0 | 0 | 9 | 2 | 4 |
| Adjuvant Phase | Withdrawal by Subject | 0 | 0 | 4 | 1 | 4 |
| Neoadjuvant Phase | Death | 1 | 2 | 0 | 0 | 0 |
| Neoadjuvant Phase | Disease Progression or Recurrence | 2 | 3 | 0 | 0 | 0 |
| Neoadjuvant Phase | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 |
| Neoadjuvant Phase | Physician Decision | 1 | 2 | 0 | 0 | 0 |
| Neoadjuvant Phase | Requirement for Alternative Therapy | 0 | 1 | 0 | 0 | 0 |
| Neoadjuvant Phase | Withdrawal by Subject | 2 | 5 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Trastuzumab | ABP 980 |
|---|---|---|---|
| Age, Continuous | 52.7 years STANDARD_DEVIATION 11 | 52.7 years STANDARD_DEVIATION 11.29 | 52.8 years STANDARD_DEVIATION 10.72 |
| Age, Customized < 50 years | 274 Participants | 134 Participants | 140 Participants |
| Age, Customized ≥ 50 years | 451 Participants | 227 Participants | 224 Participants |
| Axilla Lymph Node Involvement No | 182 Participants | 95 Participants | 87 Participants |
| Axilla Lymph Node Involvement Yes | 543 Participants | 266 Participants | 277 Participants |
| Geographic Region Eastern Europe | 544 Participants | 273 Participants | 271 Participants |
| Geographic Region Other | 92 Participants | 42 Participants | 50 Participants |
| Geographic Region Western Europe | 89 Participants | 46 Participants | 43 Participants |
| Hormone Receptor Status Estrogen and/or progesterone receptor positive | 533 Participants | 268 Participants | 265 Participants |
| Hormone Receptor Status Estrogen and progesterone receptor negative | 192 Participants | 93 Participants | 99 Participants |
| Paclitaxel Dosing Schedule Every 3 weeks | 514 Participants | 258 Participants | 256 Participants |
| Paclitaxel Dosing Schedule Every week | 211 Participants | 103 Participants | 108 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 14 Participants | 4 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 68 Participants | 36 Participants | 32 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not allowed to collect | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 656 Participants | 324 Participants | 332 Participants |
| Race/Ethnicity, Customized Other | 41 Participants | 21 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 664 Participants | 333 Participants | 331 Participants |
| Sex: Female, Male Female | 725 Participants | 361 Participants | 364 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tumor Stage T4 | 162 Participants | 80 Participants | 82 Participants |
| Tumor Stage < T4 | 563 Participants | 281 Participants | 282 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 227 / 364 | 220 / 361 | 124 / 349 | 49 / 171 | 60 / 171 |
| serious Total, serious adverse events | 18 / 364 | 5 / 361 | 18 / 349 | 6 / 171 | 6 / 171 |
Outcome results
Primary
Percentage of Participants With a Pathologic Complete Response
Pathologic complete response (pCR) was defined as the absence of invasive tumor cells in the breast tissue and in axillary lymph nodes, regardless of residual ductal carcinoma in situ (DCIS). Participants underwent a lumpectomy or mastectomy with sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND) within 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase. The pathology evaluation of surgical specimens for pCR analysis was conducted by local laboratories at the study sites.
Time frame: 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase
Population: The pCR evaluable population, which included all randomized participants who received any amount of study drug, underwent the surgery, and had a non-missing evaluable pCR assessment from the local laboratory evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABP 980 | Percentage of Participants With a Pathologic Complete Response | 48.0 percentage of participants |
| Trastuzumab | Percentage of Participants With a Pathologic Complete Response | 40.5 percentage of participants |
Comparison: The clinical equivalence between ABP 980 and trastuzumab was first evaluated by comparing the 2-sided 90% confidence interval (CI) of the Risk Difference (RD; ABP 980 - Trastuzumab) of pCR between ABP 980 and trastuzumab with a fixed margin of (-13%, 13%), estimated using a generalized linear model adjusted for stratification factors tumor (T)-stage, nodal status, hormone receptor status, planned paclitaxel dosing schedule, and geographic region.p-value: 0.050890% CI: [1.2, 13.4]Generalized linear model
Comparison: If the test of equivalence on the RD of pCR was successful, then equivalence was tested on the Risk Ratio (RR; ABP 980 / Trastuzumab) of pCR at a 2-sided significance level of 0.05 by comparing the 2-sided 90% CI of the RR of pCR between ABP 980 and trastuzumab, estimated using a generalized linear model adjusted for stratification factors: tumor (T)-stage, nodal status, hormone receptor status, planned paclitaxel dosing schedule, and geographic region.p-value: 0.04390% CI: [1.0327, 1.366]Generalized linear model
Secondary
Percentage of Participants With a Pathologic Complete Response in Breast Tissue and Axillary Lymph Nodes and Absence of DCIS
Pathological complete response was defined as the absence of invasive tumor cells in the breast tissue and axillary lymph node(s) and absence of residual DCIS. Participants underwent a lumpectomy or mastectomy with sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND) within 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase. The pathology evaluation of surgical specimens for pCR analysis was conducted by local laboratories at the study sites.
Time frame: 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase
Population: pCR evaluable population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABP 980 | Percentage of Participants With a Pathologic Complete Response in Breast Tissue and Axillary Lymph Nodes and Absence of DCIS | 37.7 percentage of participants |
| Trastuzumab | Percentage of Participants With a Pathologic Complete Response in Breast Tissue and Axillary Lymph Nodes and Absence of DCIS | 29.6 percentage of participants |
Comparison: The analysis of risk difference (ABP 980 - Trastuzumab) estimated using a generalized linear model adjusted for the randomization stratification factors T-stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographic region.p-value: 0.025390% CI: [2.1, 13.9]Generalized linear model
Comparison: The analysis of risk ratio (ABP 980 / Trastuzumab) estimated using a generalized linear model adjusted for the randomization stratification factors T-stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographic region.p-value: 0.024590% CI: [1.0673, 1.5222]Generalized linear model
Secondary
Percentage of Participants With a Pathologic Complete Response in Breast Tissue Only
Pathologic complete response (pCR) was defined as the absence of invasive tumor cells in the breast tissue, regardless of residual ductal carcinoma in situ (DCIS). Participants underwent a lumpectomy or mastectomy with sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND) within 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase. The pathology evaluation of surgical specimens for pCR analysis was conducted by local laboratories at the study sites.
Time frame: 3 to 7 weeks after the last dose of study drug in the neoadjuvant phase
Population: pCR evaluable population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABP 980 | Percentage of Participants With a Pathologic Complete Response in Breast Tissue Only | 51.1 percentage of participants |
| Trastuzumab | Percentage of Participants With a Pathologic Complete Response in Breast Tissue Only | 45.0 percentage of participants |
Comparison: The analysis of risk difference (ABP 980 - Trastuzumab) estimated using a generalized linear model adjusted for the randomization stratification factors T-stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographic region.p-value: 0.108690% CI: [-0.2, 12.2]Generalized linear model
Comparison: The analysis of risk ratio (ABP 980 / Trastuzumab) estimated using a generalized linear model adjusted for the randomization stratification factors T-stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographic region.p-value: 0.080790% CI: [1.008, 1.3035]Generalized linear model