A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Trastuzumab-MCC-DM1 (PRO132365) Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Previously Received a Trastuzumab-Containing Regimen
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 54
- 主要终点
- Number of Patients With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This is a phase I, multicenter, open-label, dose-escalation study of single-agent trastuzumab-MCC-DM1 administered by intravenous (IV) infusion in patients with HER2-positive metastatic breast cancer (MBC) who have previously received trastuzumab. The study will assess the safety, tolerability, and pharmacokinetics of trastuzumab-MCC-DM1 and determine the dose and schedule to be used in Phase II.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically documented, incurable, locally advanced or metastatic breast cancer
- •Evaluable or measurable HER2-positive disease
- •History of progression during or within 60 days after treatment with any prior trastuzumab-containing chemotherapy regimen for HER2-positive breast cancer
- •Previous treatment with chemotherapy for MBC
- •Granulocyte count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 9 g/dL
- •Serum bilirubin ≤ 1.5 mg/dL; AST, ALT, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN) except for: Patients with hepatic metastases: ALT and AST ≤ 5 × ULN Patients with hepatic and/or bone metastases: alkaline phosphatase ≤ 5 × ULN
- •Serum creatinine ≤ 1.5 mg/dL or creatinine clearance of ≥ 60 mL/min based on a 24-hour urine collection
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- •Women of childbearing potential and men must agree to use an effective method of birth control (e.g., hormonal, barrier) while receiving study treatment
排除标准
- •History of significant cardiac disease, unstable angina, CHF, myocardial infarction, or ventricular arrhythmia requiring medication
- •History of Grade ≥ 3 hypersensitivity reaction to trastuzumab
- •History of any toxicity to trastuzumab that resulted in trastuzumab being permanently discontinued
- •Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first study treatment
- •Require supplemental oxygen for daily activities
- •Grade ≥ 2 peripheral neuropathy
- •Bisphosphonate therapy for symptomatic hypercalcemia
- •Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy for the treatment of breast cancer within 4 weeks of first study treatment
- •Any experimental therapy within 4 weeks of first study treatment
- •Any major surgical procedure within 4 weeks of first study treatment
- •History of clinically symptomatic liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis
- •Pregnancy or lactation
- •Cardiac troponin I ≥ 0.2 ng/mL
- •Ejection fraction < 50% or below the lower limit of normal determined by echocardiogram or MUGA scan
- •Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent
研究组 & 干预措施
1
干预措施: trastuzumab-MCC-DM1 (Drug)
结局指标
主要结局
Number of Patients With Dose Limiting Toxicities (DLTs)
时间窗: A minimum of 21 days after first dose of trastuzumab-MCC-DM1
DLT is defined as one of the following as per investigator related to study drug: * Grade ≥ 3 non-hematologic, non-hepatic major organ toxicity * Grade ≥ 3 cardiac toxicity, including cardiac troponin I elevation or any new segmental wall abnormality as determined by non-invasive cardiac imaging * Grade ≥ 4 thrombocytopenia * Grade ≥ 4 neutropenia (absolute neutrophil count \< 500/μ L) lasting \> 4 days or accompanied by fever * Grade ≥ 4 anemia * Grade ≥ 3 serum bilirubin, hepatic transaminase (alanine aminotransferase or aspartate aminotransferase), or alkaline phosphatase For patients with Grade 2 hepatic transaminase or alkaline phosphatase levels at baseline as a result of liver metastases or bone metastases, a hepatic transaminase or alkaline phosphatase level ≥ 10 times the upper limit of normal will be considered a DLT. * Weekly cohorts only: Toxicity preventing retreatment on Cycle 1, Day 8 or toxicity preventing re-treatment on Cycle 1, Days 15 and Day 22
Maximum Tolerated Dose (MTD)
时间窗: A minimum of 21 days after first dose of trastuzumab-MCC-DM1
The highest dose level resulting in a DLT in ≤ 1 of 6 patients was declared the MTD.
Percentage of Participants With Adverse Events (AE), Serious Adverse Events (SAE), AEs With Grade >=3, and AEs Related To Treatment
时间窗: Study treatment initiation until 30 or 90 days after last administration of study treatment
The time frame for AEs is study treatment initiation until 30 days after last administration of study treatment or at the time of initiation of another anti-cancer therapy, which ever occurs first. The time frame for SAEs is study treatment initiation until 90 days after last administration of study treatment or at the time of initiation of another anti-cancer therapy, which ever occurs first.
PK Parameters After the First Dose: Terminal Half-life (t½) for T-DM1 Concentrations
时间窗: 3-Week and Weekly Cohorts: Cycle 1 Day 1 Pre-dose 30 minutes and 4 hours after the end of infusion; Cycle 1 Day 2, 3, 4, 8 (Pre-dose 30 minutes after the end of infusion) 11, 15 (Pre-dose 30 minutes after the end of infusion) and 18
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Pharmacokinetic (PK) Parameters After the First Dose: Maximum Observed Plasma Concentration Cmax for T-DM1 Concentrations
时间窗: 3-Week and Weekly Cohorts: Cycle 1 Day 1 Pre-dose 30 minutes and 4 hours after the end of infusion; Cycle 1 Day 2, 3, 4, 8 (Pre-dose 30 minutes after the end of infusion) 11, 15 (Pre-dose 30 minutes after the end of infusion) and 18
PK Parameters After the First Dose: Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-∞] for T-DM1 Concentrations
时间窗: 3-Week and Weekly Cohorts: Cycle 1 Day 1 Pre-dose 30 minutes and 4 hours after the end of infusion; Cycle 1 Day 2, 3, 4, 8 (Pre-dose 30 minutes after the end of infusion) 11, 15 (Pre-dose 30 minutes after the end of infusion) and 18
次要结局
- Percentage of Participants With an Objective Response(Baseline to the end of the study (up to 3 years 2 months))
- Duration of Objective Response(Baseline to the end of the study (up to 3 years 2 months))
- Progression-free Survival(Baseline to the end of the study (up to 3 years 2 months))
- Percentage of Participants With Anti-therapeutic Antibodies to Trastuzumab Emtansine(Baseline to the end of the study (up to 3 years 2 months))