A Randomized, Multicenter, Open-Label, Two-Arm, Phase III Neoadjuvant Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Patients With HER2-Positive Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 444
- 试验地点
- 79
- 主要终点
- Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples
研究概览
简要总结
This is a randomized, multicenter, open-label, two-arm study in treatment-naive participants with operable, locally advanced, or inflammatory, centrally-assessed HER2-positive early breast cancer (EBC) whose primary tumors were greater than or equal to (>/=) 2 centimeters (cm). The study was designed to evaluate the efficacy and safety of trastuzumab emtansine + pertuzumab (experimental arm; T-DM1 + P) versus chemotherapy, trastuzumab + pertuzumab (control arm; TCH + P). The study comprised a neoadjuvant treatment period, followed by surgery, and an adjuvant treatment period.
Treatment can be stopped due to disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Histologically confirmed invasive breast cancer with a primary tumor size of greater than (>) 2 cm
- •HER2-positive breast cancer
- •Participants with multifocal tumors (more than one tumor confined to the same quadrant as the primary tumor) are eligible provided all discrete lesions are sampled and centrally confirmed as HER2 positive
- •Stage at presentation: cT2-cT4, cN0-cN3, cM0, according to American Joint Committee on Cancer (AJCC) staging system
- •Known hormone receptor status of the primary tumor
- •Participant agreement to undergo mastectomy or breast-conserving surgery after neoadjuvant therapy
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Baseline Left Ventricular Ejection Fraction (LVEF) >/= 55 percent (%) measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA)
- •Effective contraception as defined by protocol
排除标准
- •Stage IV (metastatic) breast cancer
- •Participants who have received prior anti-cancer therapy for breast cancer except those participants with a history of breast lobular carcinoma in situ (LCIS) that was surgically managed or ductal carcinoma in situ (DCIS) treated exclusively with mastectomy. In case of prior history of LCIS/DCIS, >5 years must have passed from surgery until diagnosis of current breast cancer
- •Participants with multicentric (multiple tumors involving more than 1 quadrant) or bilateral breast cancer
- •Participants who have undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes
- •Axillary lymph node dissection or positive sentinel lymph node prior to start of neoadjuvant therapy
- •History of concurrent or previously non-breast malignancies except for appropriately treated (1) non-melanoma skin cancer and (2) in situ carcinomas, including cervix, colon, and skin. A participant with previous invasive non-breast cancer is eligible provided he/she has been disease-free >/= 5 years
- •Treatment with any investigational drug within 28 days prior to randomization
- •Current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0
- •Any significant concurrent medical or surgical conditions or findings that would jeopardize the participant's safety or ability to complete the study
- •Current pregnancy or breastfeeding
研究组 & 干预措施
Trastuzumab (TCH) + Pertuzumab
Participants will receive pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion followed by trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion followed by docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).
干预措施: Carboplatin (Drug)
Trastuzumab (TCH) + Pertuzumab
Participants will receive pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion followed by trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion followed by docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).
干预措施: Docetaxel (Drug)
Trastuzumab (TCH) + Pertuzumab
Participants will receive pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion followed by trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion followed by docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).
干预措施: Pertuzumab (Drug)
Trastuzumab (TCH) + Pertuzumab
Participants will receive pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion followed by trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion followed by docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).
干预措施: Trastuzumab (Drug)
Trastuzumab Emtansine (T-DM1) + Pertuzumab
Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
干预措施: Pertuzumab (Drug)
Trastuzumab Emtansine (T-DM1) + Pertuzumab
Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
干预措施: Trastuzumab Emtansine (Drug)
结局指标
主要结局
Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples
时间窗: Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
tpCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes ( that is \[i.e.\], ypT0/is, ypN0 in the American Joint Committee on Cancer \[AJCC\] staging system, 7th edition). Percentage of participants with tpCR was reported.
次要结局
- Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score(From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period)
- Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales(From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period)
- Event-Free Survival(From randomization up to disease progression or recurrence or death (up to approximately 47 months))
- Invasive Disease-free Survival (IDFS)(From surgery to the first documented occurrence of IDFC event (up to approximately 47 months))
- Percentage of Participants by Response for Skin Problem Single Items(Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months))
- Time to Clinically Meaningful Deterioration in GHS/QoL Score(From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period)
- Maximum Observed Serum Concentration (Cmax) of Trastuzumab(15-30 minutes (min) post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant and adjuvant period)
- Cmin of Trastuzumab Emtansine and Total Trastuzumab(Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant and adjuvant period)
- Percentage of Participants by Response for Neuropathy Single Item(Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months))
- Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations(15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period)
- Overall Survival(From randomization until death (up to approximately 47 months))
- Percentage of Participants Who Received Breast-Conserving Surgery (BCS)(Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period))
- Minimum Observed Serum Concentration (Cmin) of Trastuzumab(Pre-study treatment infusion (0 hours [hr]) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant and adjuvant period)
- Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1)(15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period)
- Percentage of Participants With ATA to Trastuzumab(Baseline (Pre-trastuzumab [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (Pre-trastuzumab infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant period)
- Time to Clinically Meaningful Deterioration in Function Subscale(From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period)
- Cmax of Trastuzumab Emtansine and Total Trastuzumab(15-30 min post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant and adjuvant period.)
- Percentage of Participants by Response for Hair Loss Single Item(Baseline,Cycle(C) 3, C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4(approx 47 months))
- Percentage of Participants With Selected Adverse Events (AEs)(Baseline to end of study (approximately 47 months))
- Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales(From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period)
- Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1(Baseline (b) (Pre-TDM1 [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (pb) (Pre-TDM1 infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant period)