A Phase I Study of Nab-paclitaxel (Abraxane), Gemcitabine, and Capecitabine (Xeloda) (AGX) in Patients With Previously Untreated, Metastatic Pancreatic Adenocarcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 2
- 主要终点
- to establish the maximal tolerated dose (MTD) of the AGX combination in patients with previously untreated, metastatic pancreatic adenocarcinoma.
研究概览
简要总结
The purpose of this study is to evaluate optimal dose and safety of the combination of Abraxane, gemcitabine, and Xeloda (capecitabine) (AGX) as first-line therapy in patients with metastatic pancreatic cancer.
详细描述
Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related mortality in the United States, with an estimated 35,240 deaths attributable to PDAC in 2009 (1). Over 90% of patients have inoperable disease at presentation, at which point systemic therapy becomes the primary form of treatment. Single agent gemcitabine became the standard of care for advanced pancreatic cancer a decade ago since demonstrating improved survival when compared with fluorouracil. Since then, a number of phase III trials have evaluated the benefit of adding additional cytotoxic or targeted agents to gemcitabine (2-17).
The PA.3 trial (15), which led to the approval of erlotinib in advanced pancreatic cancer, was a landmark study in that it represented the first positive phase III study of a combination regimen for this disease indication; however, while erlotinib represents both an important proof of principle and a welcome addition to our therapeutic armamentarium, it has failed to gain significant traction in this disease, as many in the oncology community consider the marginal absolute improvement in median overall survival to be of questionable clinical significance.
While these studies individually have failed to consistently demonstrate a survival advantage for gemcitabine-based combination therapy, a recent meta-analysis did show that the addition of either a platinum analog or a fluoropyrimidine to gemcitabine does result in a significant improvement in overall survival compared to gemcitabine alone, particularly in patients with a preserved performance status (18). As described in the following section, the combination of gemcitabine and capecitabine may be a particularly attractive cytotoxic doublet to build upon.
Gemcitabine/capecitabine for pancreatic cancer
Gemcitabine and capecitabine have demonstrated synergy in pre-clinical studies, thought to be due to several mechanisms. Capecitabine is converted to fluorouracil in tissues by pyrimidine nucleoside phosphorylase (PyNPase), which is over-expressed in many tumors (19). In breast cancer xenograft models, gemcitabine has been shown to cause increased expression of PyNPase, which may in turn enhance the conversion of capecitabine to 5-FU (20). An intermediate of gemcitabine also leads to enhanced binding of the active metabolite of 5-FU to thymidylate synthase, further augmenting the action of capecitabine (21).
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
- 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 pancreatic adenocarcinoma
- •Stage IV disease (metastatic only)
- •No prior systemic therapy for their diagnosis (except in adjuvant setting > six months previously)
- •ECOG performance score of 0-1
- •At least 18 years of age
- •Evidence of either or both of the following:
- •RECIST-defined measurable disease (lesions that can be accurately measured in at least one dimension with the longest diameter ≥ 20mm using conventional techniques or ≥10 mm with spiral CT scan)
- •An elevated serum CA19-9 at baseline ( ≥ 2X ULN)
- •Female patients must be either surgically sterile or postmenopausal, or if of childbearing potential must have a negative pregnancy test (serum or urine) prior to enrollment and agree to use effective barrier contraception during the period of therapy. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the investigator.
- •Adequate bone marrow function:
- •ANC ≥ 1500/uL
- •platelet count ≥ 100,000/uL
- •hemoglobin ≥ 9.0 g/dL
- •Total bilirubin ≤ 1.5 X ULN
- •AST (SGOT) ≤ 2.5 X ULN
- •ALT (SGPT) ≤ 2.5 X ULN
- •Adequate renal function as determined by either:
- •Calculated or measured creatinine clearance ≥ 40 mL/min (for calculated creatinine clearance, Cockroft-Gault equation will be used). The Modified Cockcroft-Gault formula is as follows:
- •((140 - age(yrs)) x (actual weight(kg))) / (72 x serum creatinine(mg/dl))
- •Multiply by another factor of 0.85 if female
- •Serum creatinine ≤ 1.5 X ULN
- •Ability to swallow oral medications
- •Ability to understand the nature of this study protocol and give written informed consent
- •Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
排除标准
- •Any prior systemic or investigational therapy for metastatic pancreatic cancer. Systemic therapy administered alone or in combination with radiation in the adjuvant setting is permissible as long as it was completed > 6 months prior to the time of study enrollment.
- •Inability to comply with study and/or follow-up procedures.
- •History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that, in the opinion of the investigator, renders the subject at high risk from treatment complications or might affect the interpretation of the results of the study.
- •Presence of central nervous system or brain metastases.
- •Life expectancy < 12 weeks
- •Pregnancy (positive pregnancy test) or lactation.
- •Prior malignancy except for adequately treated basal cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other form of cancer from which the patient has been disease-free for 5 years.
- •Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months.
- •Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.
- •Known, existing uncontrolled coagulopathy.
- •Pre-existing sensory neuropathy > grade
- •Major surgery within 4 weeks of the start of study treatment, without complete recovery.
- •Concurrent/pre-existing use of coumadin.
研究组 & 干预措施
Nab-paclitaxel,Gemcitabine, and Capecitabine
干预措施: nab-paclitaxel, gemcitabine, capecitabine (Drug)
结局指标
主要结局
to establish the maximal tolerated dose (MTD) of the AGX combination in patients with previously untreated, metastatic pancreatic adenocarcinoma.
时间窗: Ongoing evaluation through sequential dose cohorts
次要结局
- To assess the safety profile of this combination (AGX) using NCI-CTCAE v.4 criteria.(Ongoing evaluation for all patients throughout the course of treatment)
- To obtain a preliminary assessment of the clinical efficacy of AGX as measured by time to tumor progression, overall survival, objective radiographic response (ORR), and CA 19-9 biomarker response(Efficacy evaluations at 2-month intervals; patients followed for survival throughout lifetime.)