A Multicenter, Multinational, Phase II Study to Evaluate Perjeta in Combination With Herceptin and Standard Neoadjuvant Anthracycline-Based Chemotherapy in Patients With HER2-Positive, Locally Advanced, Inflammatory, or Early-Stage Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 401
- 试验地点
- 80
- 主要终点
- Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period
研究概览
简要总结
This multicenter, non-randomized, open-label, phase 2 study is designed to evaluate the safety and efficacy of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and anthracycline-based chemotherapy as neoadjuvant treatment in participants with HER2-positive locally advanced, inflammatory, or early-stage breast cancer. Each investigator will choose a treatment regimen (A or B) for all of their participants to follow. Treatment regimen A (for Cohort A) will include dose-dense doxorubicin and cyclophosphamide (ddAC), followed by paclitaxel, with pertuzumab and trastuzumab given from the start of paclitaxel. Treatment regimen B (for Cohort B) will include 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by docetaxel, with pertuzumab and trastuzumab given from the start of docetaxel. Participants in both cohorts will subsequently undergo surgical treatment and then resume pertuzumab and trastuzumab treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female participants with locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer. Participants with inflammatory breast cancer must be able to have a core needle biopsy
- •Primary tumor greater than (>) 2 centimeters (cm) in diameter, or > 5 millimeters (mm) in diameter and node-positive
- •HER2-positive breast cancer confirmed by a central laboratory
- •Availability of tumor tissue specimen
- •Baseline LVEF greater than or equal to (>/=) 55%
- •Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (</=) 1
- •At least 4 weeks since major unrelated surgery, with full recovery
- •Women of childbearing potential and male participants with partners of childbearing potential must agree to use a "highly effective" non-hormonal form of contraception or two "effective" forms of non-hormonal contraception by the patient and/or partner. Contraception must continue for the duration of study treatment and for at least 7 months after the last dose of study treatment
排除标准
- •Metastatic disease (Stage IV) or bilateral breast cancer
- •Participants who have had an incisional biopsy of the primary tumor or the primary tumor excised
- •Prior breast or non-breast malignancy within 5 years prior to study entry, except for carcinoma in situ and basal cell and squamous cell carcinoma of the skin. Participants with malignancies occurring more than 5 years prior to study entry are permitted if curatively treated
- •Any previous systemic therapy (including chemotherapy, immunotherapy, HER2 targeted agents, and antitumor vaccines) for cancer, or radiation therapy for cancer
- •Participants with a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) are not allowed to enter the study if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast (they are allowed to enter the study if treated with surgery alone)
- •High-risk participants who have received chemopreventive drugs in the past are not allowed to enter the study
- •Inadequate bone marrow, renal, or liver function
- •History or evidence of cardiovascular condition
- •Dyspnea at rest or other diseases that require continuous oxygen therapy
- •Severe, uncontrolled systemic disease
- •Participants with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications
- •Pregnancy or breast-feeding women
- •Participants who received any investigational treatment within 4 weeks of study start
- •Participants with known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
- •Current chronic daily treatment with corticosteroids (dose >10 mg methylprednisolone or equivalent [excluding inhaled steroids])
- •Known hypersensitivity to any of the study drugs or excipients
研究组 & 干预措施
Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Cyclophosphamide (Drug)
Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Doxorubicin (Drug)
Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Paclitaxel (Drug)
Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Pertuzumab (Drug)
Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Trastuzumab (Drug)
Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: 5-Fluorouracil (Drug)
Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Cyclophosphamide (Drug)
Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Docetaxel (Drug)
Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Epirubicin (Drug)
Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Pertuzumab (Drug)
Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
干预措施: Trastuzumab (Drug)
结局指标
主要结局
Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period
时间窗: From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks)
LVEF significant decline was defined as the decline in LVEF of \>/= 10%-points from baseline to an LVEF of \< 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results include events with onset from the first dose of pertuzumab or trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab or trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever is later.
Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Neoadjuvant Treatment Period
时间窗: From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks)
Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from first dose of pertuzumab/trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab/trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever was later.
次要结局
- Overview of the Number of Participants With at Least One Adverse Event During the Neoadjuvant Period(From first dose of any study drug prior to surgery through the day before the first dose of study drug after surgery (up to 25 weeks))
- Percentage of Participants Positive for Anti-Therapeutic Antibodies (ATAs) to Pertuzumab at Baseline and Anytime Post-Baseline(Screening (baseline) then prior to pertuzumab infusion (Hour 0) in Cycles 5, 14, 18 thereafter anytime between Cycle 8 Day 21 and surgery, up to treatment completion visit (cycle length=2-3 weeks; up to approximately 1 year, 3 months))
- Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Treatment-Free Follow-Up Period(From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years))
- Overview of the Number of Participants With at Least One Adverse Event During the Adjuvant Period(From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks))
- Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Adjuvant Treatment Period(From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks))
- Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Treatment-Free Follow-Up Period(From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years))
- Percentage of Participants With Total Pathologic Complete Response (tpCR), Evaluated After Surgery(After completion of neoadjuvant treatment and surgery (up to 25 weeks))
- Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period(From Baseline until disease progression or death due to any cause up to 24 weeks (during the neoadjuvant treatment period; assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks]))
- Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Adjuvant Treatment Period(From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks))
- Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1 to 5 Years, Determined by the Investigator According to RECIST v1.1(At 1, 2, 3, 4, and 5 years)
- Overview of the Number of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period(From 42 days after the last dose of study treatment until the end of treatment-free follow-up (TFFU; up to 5 years))
- Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Invasive Disease-Free Survival (iDFS) at 1 to 4 Years, Determined by the Investigator According to RECIST v1.1(At 1, 2, 3, and 4 years)
- Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1 to 5 Years(At 1, 2, 3, 4, and 5 years)