Phase II Study of Lapatinib and Trastuzumab Followed by Concurrent Lapatinib, Trastuzumab, and Paclitaxel Followed by Surgery for Primary HER2-positive (HER2+) Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 3
- 主要终点
- Expression of ALDH1 and CD44v Change in the Binary Biomarkers From Baseline to 6 Weeks and 18 Weeks
研究概览
简要总结
This phase II trial studies how well giving lapatinib ditosylate together with trastuzumab, paclitaxel, and surgery works in treating patients with breast cancer. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.
详细描述
PRIMARY OBJECTIVES:
I. To evaluate the changes in cancer stem cell (CSC) markers; % CD44 variant (CD44v)-positive tumor cells and aldehyde dehydrogenase-1 (ALDH1) positivity before and after study drug exposure and after concurrent preoperative chemotherapy.
II. To determine the pathological complete response (pCR) rate produced by lapatinib (lapatinib ditosylate) + trastuzumab followed by concurrent preoperative lapatinib, trastuzumab, and paclitaxel chemotherapy for operable human epidermal growth factor receptor 2-positive (HER2+) breast cancer.
SECONDARY OBJECTIVES:
I. To determine the cellular response rate produced by study drug exposure and/or concurrent preoperative chemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically or cytologically confirmed primary invasive breast cancer
- •Primary tumor is larger than 2 cm in diameter (T2) as measured by caliper or ultrasound
- •Overexpression and/or amplification of HER2 is confirmed by immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) + when IHC 2+
- •Patients have not received prior therapies for breast cancer
- •Patients have Karnofsky >= 70%
- •Leukocytes >= 3,000/mcL
- •Absolute neutrophil count >= 1,500/mcL
- •Hemoglobin >= 9.0 g/dL
- •Platelets >= 75,000/mcL
- •Total bilirubin =< 1.5 times institutional upper limit of normal
- •Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase[SGPT]) =< 2.5 times institutional ULN
- •Creatinine =< 1.5 times institutional upper limit of normal (ULN)
- •Patients must have left ventricular ejection fraction (LVEF) >= 50% by multi-gated acquisition (MUGA) or echocardiography
- •Patients must be able to take oral medications (i.e., no uncontrolled vomiting, inability to swallow, or diagnosis of chronic malabsorption)
- •Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation as well as for at least 6 months after the last dose of trastuzumab
- •Ability to understand and willingness not only for treatment but also for undergoing serial biopsies and sign a written informed consent document
- •Only Japanese women are eligible for the trial
排除标准
- •Patients who have had chemotherapy or radiotherapy
- •Patients who are receiving any other investigational agents
- •Patients have distal metastasis (stage IV disease)
- •Patients with previous (within 10 years) or current history of malignant neoplasm except for curatively treated basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- •Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib or other agents used in study
- •Patients receiving any medications or substances that are inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) are ineligible
- •Patients who have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women
- •Patients who have family or personal history of congenital long or short QT syndrome, Brugada syndrome, QT/QTc prolongation, or torsade de pointes
- •Patients who have chronic gastrointestinal disease presenting with diarrhea (inflammatory bowel disease, malabsorption, or >= grade 2 diarrhea of any etiology at baseline)
- •Patients who have neuropathy >= grade 2 of any cause
- •Patients are diagnosed with inflammatory breast cancer or bilateral breast cancer
研究组 & 干预措施
Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.
干预措施: lapatinib ditosylate (Drug)
Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.
干预措施: paclitaxel (Drug)
Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.
干预措施: trastuzumab (Biological)
Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.
干预措施: therapeutic conventional surgery (Procedure)
Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.
干预措施: pharmacological study (Other)
Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Expression of ALDH1 and CD44v Change in the Binary Biomarkers From Baseline to 6 Weeks and 18 Weeks
时间窗: From baseline to 18 weeks
For biomarkers ALDH1 and CD44v, the change in the proportions of CD44v-positive (CD44v+) tumor cells and ALDH1-positive (ALDH1+) tumor cells in tumor tissue from baseline to 6 weeks and 18 weeks time points were determined for each patient. For biomarker change, changes in the binary biomarkers between time points were assessed using McNemar's test in all patients and separately in patients with and without pCR.
Number of Participants With Pathological Complete Response (pCR)
时间窗: Up to 12 weeks
The point estimate of the pCR rate will be calculated for all patients. pCR is defined as the abscence of invasive cancer in the breast and regional lymph nodes following neoadjuvant chemotherapy.
次要结局
- Number of Participants With Treatment-Related Toxicities(Up to 12 weeks after completion of study treatment)
- Cellular Response Rate, Defined as Patients With an Epithelial Phenotype Having Eradication of CTCs; Patients With a Mesenchymal Phenotype Having Eradication of Tumor Cells; Patients With a Mesenchymal Phenotype Converting to an Epithelial Phenotype(Up to 18 weeks)
- EGFR-mutation Status of Tumors and Changes in the Ratio of Phosphorylated to Nonphosphorylated HER2, EGFR, ERK, Akt, and the Ki67 and TUNEL Indices Before and After Treatment(From baseline to 24 weeks)