A Multi-Institutional, Single Arm, Two-Stage Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- PrECOG, LLC.
- 入组人数
- 74
- 试验地点
- 25
- 主要终点
- Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months)
研究概览
简要总结
Patients with advanced or metastatic cholangiocarcinoma (CCA) who are not eligible for curative surgery, transplantation, or ablative therapies will receive nab-paclitaxel and gemcitabine chemotherapy.
The purpose of this study is to evaluate the effectiveness and safety of the combination of nab-paclitaxel and gemcitabine. The effectiveness will be determined by improvement in the length of time during and after treatment, that the CCA does not get worse.
详细描述
Advanced cholangiocarcinomas (CCAs) are aggressive tumors with median survival time after diagnosis of less than 12 months, and five-year overall survival (OS) of ~5% with systemic chemotherapy. Currently available systemic therapies for CCA are largely ineffective, thus the rationale for the proposed research is to investigate targeted delivery of chemotherapy.
The goal of this study is to evaluate the efficacy of gemcitabine plus nab-paclitaxel in patients with advanced CCA. This is based on the premise that nab-paclitaxel binds to SPARC (secreted protein acidic and rich in cysteine) through its interaction with albumin, leading to an increase in intra-tumoral concentration of gemcitabine through decreased deoxycytidine deaminase (CDA) enzyme. We hope to improve on the OS of patients with advanced CCA through the use of the synergistic combination of nab-paclitaxel and gemcitabine to specifically target the SPARC protein in the peri-tumoral stroma. We aim to provide critical data to further develop pharmacologic strategies to target the desmoplastic stroma in order to increase chemotherapy responsiveness of CCAs.
We will also examine whether circulating tumor cell (CTC) levels with targeted gene expression analysis and stromal SPARC levels correlate with patient outcome and thus serve as prognostic biomarkers. We will evaluate the role of Human Equilibrative Nucleoside Transporter 1 (hENT1), CDA and tumor fibrosis as additional prognostic and predictive biomarkers in CCA. This clinical trial hopes to improve on the poor prognosis of patients with advanced CCA by establishing the activity of a platinum-free doublet, nab-paclitaxel plus gemcitabine that has shown clear clinical benefit in pancreatic cancer which has close biological parallels to CCA.
A maximum of 70 patients will be enrolled to attain 67 eligible/evaluable patients. Stage I will enroll 37 patients. If 21 or more patients are alive and progression-free at 6 months, the study will proceed to Stage II and an additional 33 patients will be enrolled.
Procurement of archived tissue, if available, from a previous diagnostic biopsy is mandatory for enrollment. If not available, this will not preclude participation in the trial, nor will additional biopsies be performed for research purposes only.
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
- •Must have histologically-confirmed diagnosis of cholangiocarcinoma Stage II, III, or IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed.
- •Must have radiographically measurable disease in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures; a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable.
- •May have received prior radiation, chemoembolization, radioembolization, or other local ablative therapies, or hepatic resection if completed ≥ 4 weeks prior to registration AND if patient has recovered to ≤ grade 1 toxicity. NOTE: Measurable disease (as required above) must still be present.
- •May have received prior radiation for bone or brain metastases if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) ≥ 2 weeks prior to registration.
- •Age ≥ 18 years.
- •Child-Pugh score of A or B with ≤ 7 points.
- •Eastern Cooperative Oncology Group performance status of 0-
- •Willing to provide archived tissue, if available, from a previous diagnostic biopsy.
- •Must be able to tolerate CT and/or MRI with contrast.
- •Adequate organ function obtained ≤ 2 weeks prior to registration:
- •Absolute Neutrophil Count ≥ 1500/mm³
- •Hemoglobin ˃9.0 g/dL
- •Platelets ˃100,000/mm³
- •Serum Creatinine ≤ 1.5x Upper Limit Normal (ULN)
- •Creatinine Clearance ≥ 50 mL/min
- •Albumin ≥ 2.8 g/dL
- •Total Bilirubin ≤ 1.5 mg/dL or ≤ 1.5x ULN
- •Aspartate Aminotransaminase (AST)/Alanine Aminotransaminase (ALT) ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)
- •International Normalized Ratio (INR) <1.5x the ULN [INR ≥ 1.5 is allowed if anticoagulation is used.]
- •Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine may harm the fetus or child.
- •Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for this cancer.
- •Must not be receiving treatment with other investigational agents.
- •Must not have a pre-existing >grade 2 peripheral neuropathy.
- •Must not be receiving immunosuppressive medications, including systemic corticosteroids, aside from the following exceptions: used for adrenal replacement, appetite stimulation, therapy for asthma, bronchitis exacerbation (≤ 2 weeks), anti-emesis, or pre-medication for procedures (i.e. CT scan).
- •No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) seropositivity.
- •Must not have undergone liver transplantation.
- •Must not have serious non-healing wound, ulcer, bone fracture, or abscess.
- •Must not have undergone a major surgical procedure <4 weeks prior to registration.
- •Must not have possible histories of pneumonitis or pneumonitis risk factors.
- •Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
- •Must have no ongoing or active, uncontrolled infections.
- •Must have no evidence of significant, uncontrolled concomitant diseases including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months, uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, connective tissue disease including lupus.
- •Must not have any history of allergic reaction(s) attributed to compounds of similar composition to nab-paclitaxel or gemcitabine.
排除标准
- 未提供
研究组 & 干预措施
Nab-Paclitaxel and Gemcitabine
Nab-Paclitaxel 125 mg/m² IV and Gemcitabine 1000 mg/m² on days 1, 8 and 15 every 28 days until progression or unacceptable toxicity.
干预措施: Nab-Paclitaxel and Gemcitabine (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months)
时间窗: Assessed at 6 months
Progression-free survival is defined as the time from the date of first study treatment to either the date of documented disease progression or death from any cause, whichever occurred first. Progression-free survival rate at 6 months is defined as the proportion of patients who were disease progression-free and alive at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameter/axes of target lesions, taking as reference the smallest sum on study, or unequivocal progression of existing non-target lesions, or the appearance of new lesions.
次要结局
- Overall Survival (OS)(Every 3-6 months for up to 3 years)
- Progression-free Survival (PFS)(Every 3-6 months for up to 3 years)
- Overall Response Rate (ORR)(Every 3-6 months for up to 3 years)
- Time To Progression (TTP)(Every 3-6 months for up to 3 years)
- Disease Control Rate (DCR)(Every 3-6 months for up to 3 years)
- Association Between PFS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline(CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment)
- Association Between OS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline(CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment)