Phase I-II Study of Trastuzumab in Combination With RAD001 in Patients With HER-2 Overexpressing, PTEN-deficient Metastatic Breast Cancer Progressing on Trastuzumab-Based Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Optimal Dose of RAD001 in Combination With Trastuzumab (Phase I)
研究概览
简要总结
Primary Objectives:
-
To identify the optimal dose and pharmacokinetics of RAD001 in combination with trastuzumab in a Phase I trial
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To determine the efficacy of RAD001 plus trastuzumab in HER-2-overexpressing patients with resistance to trastuzumab-based therapy for metastatic breast cancer in a Phase II trial.
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Trastuzumab resistance will be defined as the development of progressive disease after trastuzumab-based therapy for metastatic breast cancer. Patients who develop metastases while receiving adjuvant or neoadjuvant trastuzumab will be eligible.
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Efficacy would be measured by the rate of objective response plus stable disease lasting 6 months (complete response (CR) + partial response (PR) + stable disease SD).
Secondary objectives:
- To determine the pharmacokinetics of RAD001 in combination with trastuzumab. In the phase II portion of the study, pharmacokinetic studies will be optional.
- To determine the nature and degree of toxicity of RAD001 in combination with trastuzumab in this cohort of patients
- To determine expression levels of total and phosphorylated mTOR and p70S6K-T389-P as well as relevant downstream signaling components (e.g., S6, 4E-BP1) in pre- and post- treatment tumor samples.
- To correlate biomarker expression with response to therapy.
详细描述
RAD001 is a new drug that was designed to block proteins that are important in the development and growth of cancer. It may also stop the growth of new blood vessels that help tumor growth, resulting in cell death.
Trastuzumab is a monoclonal antibody that binds to the HER-2 molecule on the surface of cancer cells. It does not bind to cells that do not have the HER-2 molecule. Trastuzumab slows the growth of cancer cells and also makes them more able to be treated with other chemotherapy drugs.
Before you begin to receive the study drug, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have your complete medical history recorded, and a physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate) will be performed. Routine blood tests (about 2 teaspoons) will be collected within 1 week before therapy. Cancer tissue taken at the time of your initial diagnosis or surgery will be collected. Special stains will be done that will help find ways in which researchers can predict the response of your cancer to trastuzumab plus RAD001. Women who are able to have children must have a negative urine pregnancy test. Some participants may need x-rays and/or positron emission tomography (PET) scans before receiving study drug and again within 3 weeks after the start of therapy.
If you are found to be eligible to take part in this study, you will receive RAD001 tablets by mouth once a day. Every 3 weeks (21 days) is considered 1 course of the study. The dose of trastuzumab you receive on this study will not be different from what you were receiving before this study started.
If you are participating in the Phase I portion of the study, you will have about 4 teaspoons of blood drawn before you start the study on Day 1. Blood samples will be drawn prior to initiation of treatment and at 0.5, 1, 2, 5, 8, 24 hours. You will also have around 4 teaspoons of blood drawn on Day 15 (before the start of treatment and at 0.5, 1, 2, 5, 8, and 24 hours).
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •History of biopsy-proven HER-2-overexpressing breast cancer and radiographic evidence of metastatic disease. The HER-2 status can be determined either by immunohistochemistry (score, 3+) or by fluorescence in situ hybridization.
- •History of trastuzumab resistance, defined as the development of progressive disease after trastuzumab-based therapy for metastatic breast cancer. Patient may not have received more than 2 prior trastuzumab-based regimens and one lapatinib-based regimen (either as single agent or in combination with chemotherapy)for metastatic breast cancer. Patients who develop metastatic disease during or after adjuvant or neoadjuvant trastuzumab are eligible.
- •Performance status 0-2 (by Eastern Cooperative Oncology Group (ECOG) scale).
- •Absolute neutrophil count (ANC) 1500/µl or higher; Platelets 100,000/µl or higher; Hemoglobin 9.0 gm/dL or higher; Serum creatinine 2.0 mg/dL or lower; Total bilirubin 1.5 mg/dL or lower; Serum glutamic pyruvic transaminase (SGPT) up to 3* upper limit of normal; Alkaline phosphatase up to 3* upper limit of normal; Calcium 11.0 mg/dL or lower.
- •Age 18 years or older.
- •Patients must not be pregnant. A pregnancy test will be obtained if the patient is a woman of child-bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months).
- •Patients must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment.
- •Patients must have measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST). Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension with longest diameter >/= 20 mm using conventional techniques or >/= 10 mm with spiral computed tomography (CT) scan.
- •Patients may not be receiving any other investigational agents, and must not have received investigational agents within 15 days of enrollment.
- •Left ventricular ejection fraction determined by echocardiogram or multigated acquisition (MUGA) (cardiac scan) must be 50% or higher.
排除标准
- •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
- •Prior treatment with any investigational drug within the preceding 15 days
- •Chronic treatment with systemic steroids or another immunosuppressive agent
- •Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases, and patients diagnosed with brain mets or leptomeningeal disease (LMD) within 3 months.
- •Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
- •A known history of HIV seropositivity
- •Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
- •Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin)
- •Patients who have received prior treatment with an mTor inhibitor.
- •History of noncompliance to medical regimens.
- •Patients unwilling to or unable to comply with the protocol.
- •Patients who are receiving any other investigational agents
- •Patients exhibiting confusion, disorientation, or having a history of major psychiatric illness that may impair the understanding of the informed consent.
研究组 & 干预措施
Trastuzumab + RAD001
Trastuzumab loading dose is 8 mg/kg daily; maintenance dose = 6 mg/kg once per 21 day cycle. Starting RAD001 dose 10 mg by mouth daily.
干预措施: RAD001 (Drug)
Trastuzumab + RAD001
Trastuzumab loading dose is 8 mg/kg daily; maintenance dose = 6 mg/kg once per 21 day cycle. Starting RAD001 dose 10 mg by mouth daily.
干预措施: Trastuzumab (Drug)
结局指标
主要结局
Optimal Dose of RAD001 in Combination With Trastuzumab (Phase I)
时间窗: Following two 3 week cycles of therapy
In Phase I, two dose levels of RAD001 were studied: 10 mg (dose level 1) and 5 mg (dose level -1) where each dose was evaluated after cycle 1. At MDACC, the Continual Reassessment Method (CRM) for determining Maximum Tolerated Dose (MTD) was applied to the two predefined RAD001 dose levels; and at DFCI/BIDMC, a 3 x 3 study design was utilized. Optimal dose defined as the dose most closely associated with a toxicity rate of 0.20, and toxicity defined as any grade 3 or 4 toxicity (based on Common Terminology Criteria (CTC) version 3.0 except fatigue. Participants underwent clinical evaluation every 3 weeks (one cycle) and radiologic evaluations every 6 weeks. After the second cycle, participants underwent a radiologic evaluation using the same imaging technique used at initial evaluation (ie, computed tomography or magnetic resonance imaging).
Clinical Benefit Response Rate (CBR)
时间窗: 6 weeks
Efficacy measured by the clinical benefit response rate (CBR), defined as confirmed Complete Response (CR) plus Partial Response (PR) at any time plus Persistent Stable Disease (pSD). Confirmed CR is defined as disappearance of all target lesions at the time of radiographic evaluation; pSD was defined as SD lasting 24 weeks. Complete Response (CR): disappearance of all target lesions, and Partial Response (PR): at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as a reference the baseline sum LD. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as references the smallest sum LD since the treatment started.
次要结局
未报告次要终点