Phase II Randomised, Double Blind, Placebo Controlled Trial of Neoadjuvant Artesunate in Stage II/III Colorectal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 200
- 试验地点
- 8
- 主要终点
- Recurrence free survival at 2 years
研究概览
简要总结
This study evaluates the safety and effectiveness of pre-operative artesunate given orally once a day for 14 days prior to surgery in patients with Stage II/III colorectal cancer.
Artesunate is an established antimalarial drug with an excellent safety profile, is well tolerated and affordable. A number of laboratory studies and one small pilot clinical study in patients with colorectal cancer have shown that artesunate can reduce the proliferation and growth of cancer cells.
Two hundred patients diagnosed with Stage II/III operable colorectal cancer will be randomly allocated to receive oral artesunate 200mg daily or a matching placebo for 14 days prior to surgery. Patients will be followed up closely for 5 years to see if giving artesunate preoperatively reduces the risk of cancer recurring after surgery.
详细描述
Artesunate is an established antimalarial drug belonging to the artemisinin class of drugs, has an excellent safety profile, is well tolerated and affordable. In last two decades, artemisinins have shown potent and broad anticancer properties in a range of cell lines and animal models, supporting the hypothesis that artemisinins have the potential to be an effective anti-cancer therapy. Multiple potential mechanisms of action include anti-proliferative effects through cell-cycle disruption, reactive oxygen species (ROS) -induced DNA damage, induction of apoptosis, anti-angiogenesis, immunomodulation and induced radiosensitivity.
Despite a multi-modality treatment approach to colorectal cancer, 5 year overall survival does not currently exceed 60%. Neoadjuvant pre-operative therapy may be more effective at eradicating micrometastases compared to adjuvant therapy delivered following the delay and immunological stress of surgery. However current neoadjuvant chemotherapy regimens are often associated with significant side effects and may result in a delay in surgery whilst patients recover. A well tolerated, affordable, novel anticancer agent that could be given to patients whilst they wait for surgery, without causing a surgical delay due to treatment related toxicity, would have a significant clinical impact on patient care.
The NeoART trial is a phase II multicentre randomised, double blind, placebo controlled trial (RCT) for patients undergoing primary surgery for Stage II/III colorectal cancers. Patients are randomised (1:1 ratio) to receive either a two week course of neoadjuvant artesunate 200mg once daily or matching placebo. Both patients and health care professionals are blinded to treatment allocation arm to minimise outcome-reporting bias. The primary endpoint of the trial is recurrence free survival two years after surgery. Secondary endpoints include 2 and 5 year overall survival, treatment related toxicity, tolerability and patient quality of life. A translational sub-study looking at predictive and prognostic biomarkers is also planned.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Artesunate
Artesunate 200mg oral tablets once daily for 14 days.
干预措施: Artesunate 200mg (Drug)
Matching placebo
Matching placebo oral tablets once daily for 14 days.
干预措施: Placebo (Drug)
结局指标
主要结局
Recurrence free survival at 2 years
时间窗: 2 years following study randomisation.
次要结局
- Recurrence free survival at 5 years(5 years from study randomisation)
- Overall survival at 2 and 5 years(2 and 5 years from study randomisation)
- Colon cancer specific death at 2 and 5 years(2 and 5 years from study randomisation)
- Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0(Assessment 60 months following study intervention)
- Pathological assessment of tumour regression (involvement of lymph nodes; serosa; resection margin)(Post surgical pathology review (following Day 14 of study intervention))
- Patient quality of life(Assessment at Day 42 of study intervention)
- Immunohistochemical analyses of paraffin-embedded tumour sections to assess Mismatch Repair (MMR) status(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Number of patients experiencing artesunate drug related toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0(Assessment at Day 42 following start of study intervention (artesunate/matching placebo))
- Surgical complications(From time of surgery up to 3 months post surgery)
- Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy(Assessment at Day 42 of study intervention)
- Immunohistochemical analyses of paraffin-embedded tumour sections to assess Kirsten rat sarcoma viral oncogene homolog (Kras) mutation status(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Immunohistochemical analyses of paraffin-embedded tumour for v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation status(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Immunohistochemical analyses of paraffin-embedded tumour for Platelet derived growth factor (PDGF) expression(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Immunohistochemical analyses of paraffin-embedded tumour for Vascular endothelial Growth Factor (VEGF) expression(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Immunohistochemical analyses of paraffin-embedded tumour for Platelet derived growth factor receptor (PDGFR) expression(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Immunohistochemical analyses of paraffin-embedded tumour on Vascular endothelial Growth Factor Receptor (VEGFR) expression(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Determination of proliferative activity (Ki-67 staining, Cluster of Differentiation 31 protein (CD31) staining)(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Determination of activation of the Deoxyribonucleic acid damage response (DDR) pathway(Pre and post intervention tumour samples from patients (Day 0 and Day 15))
- Wnt/β-catenin proliferation pathway protein expression (e.g. c-myc and cyclinD1 proteins)(Pre and post intervention tumour samples from patients (Day 0 and Day 15))