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
- 尚未招募
- 发起方
- 入组人数
- 120
- 试验地点
- 6
- 主要终点
- Recurrence-Free Survival (RFS) at 2 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation
研究概览
简要总结
TThis 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. It is well tolerated, affordable, and widely available. Several 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.
One hundred patients diagnosed with Stage II/III operable colorectal cancer will be randomly allocated to receive oral artesunate 200 mg daily or a matching placebo for 14 days prior to surgery. Patients will then be followed closely for 5 years to determine whether pre-operative artesunate reduces the risk of cancer recurrence 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
- Quadruple (Participant, Care Provider, 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
- •Aged 18 or over
- •Histologically proven single primary site colorectal adenocarcinoma or high grade dysplasia plus unequivocal radiological evidence of invasive cancer
- •Stage II/III colorectal cancer planned for surgical resection and no clinical indication for neoadjuvant preoperative chemotherapy/chemoradiation therapy
- •WHO performance status 0,1 or 2
- •Adequate full blood count: White Cell Count (WCC) >3.0 x 109 /l; Platelets >100 x 109/l; Haemoglobin (Hb) >80g/L
- •Adequate renal function : Glomerular Filtration Rate >30ml/min by Cockcroft-Gault formula.
- •Adequate hepatobiliary function : Total bilirubin < 3 x Upper limit norm
- •Female participants of childbearing potential must have a negative pregnancy test <72 hours prior to initiating study intervention and agree to avoid pregnancy using adequate, medically approved contraceptive precautions for up to 6 weeks after the last dose of study treatment interventions.
- •Male participants with a partner of childbearing potential must agree to use adequate, medically approved contraceptive precautions during and for up to 6 weeks after the last dose of the study treatment intervention.
- •Patient able and willing to provide written, informed consent for the study.
排除标准
- •Contraindication to use of artesunate due to hypersensitivity
- •Pregnancy or lactation
- •Male or female participants unwilling to use an effective method of birth control (either hormonal in the form of the contraceptive pill or barrier method of birth control accompanied by the use of a proprietary spermicidal foam/gel or film) ; or agreement of true abstinence from time consent is signed until 6 weeks after the last dose of study treatment intervention (i.e. withdrawal, calendar, ovulation, symptothermal and post ovulation are not acceptable methods)
- •History of hearing or balance problems
- •History of immunosuppression
- •Patient weight < 52 kg or > 110 kg
- •Other planned intervention, apart from standard of care
- •Any other malignant disease diagnosis within the preceding 2 years with the exception of non-melanomatous skin cancer and carcinoma in situ
- •Lactose intolerance
研究组 & 干预措施
Artesuante
Artesunate 200mg oral tablets once daily for 14 days.
干预措施: Artesunate (Drug)
Artesunate matching placebo
Matching placebo oral tablets once daily for 14 days.
干预措施: Artesunate matching Placebo (Drug)
结局指标
主要结局
Recurrence-Free Survival (RFS) at 2 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation
时间窗: 2 years following study randomisation.
RFS is defined as the time from randomisation to the first documented recurrence of colorectal cancer (local or distant) or death from any cause, whichever occurs first. Recurrence will be assessed using standard CT scans of the chest, abdomen, and pelvis, clinical examination and measuring carcinoembryonic antigen (CEA). Confirmation of recurrence may include histological evidence where clinically indicated. Unit of Measure: Months
次要结局
- Colon Cancer-Specific Mortality at 2 and 5 Years Post-Randomisation(2 years and 5 years following study randomisation.)
- Recurrence-Free Survival at 5 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation(5 years from study randomisation)
- Overall Survival (OS) at 2 and 5 Years Post-Randomisation(2 years and 5 years following study randomisation.)
- Incidence of Artesunate-Related Toxicity Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0(Assessment at Day 42 following initiation of study intervention (artesunate or matching placebo).)
- Incidence of Artesunate-Related Toxicity Assessed by Common Terminology CTCAE v5.0(Assessment at Day 14 following initiation of study intervention (artesunate or matching placebo).)
- Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0(Assessment at Day 7 following administration of study intervention (artesunate or matching placebo).)
- Incidence Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Day 14(Assessment at Day 14 following study intervention)
- Incidence of adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0(Assessment at Day 42 following study intervention)
- Pathological assessment of tumour regression post intervention(Post surgical pathology review (following Day 14 of study intervention))
- Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires at Baseline(Assessment at Day 1 of study intervention (baseline assessment))
- Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires(Assessment at Day 7 of study intervention)
- 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)
- Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires post intervention(Assessment at Day 14 of study intervention)
- Incidence of Surgery-Related Adverse Events Assessed by CTCAE v5.0(From time of surgery up to 3 months post surgery)
- 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 sections to assess Mismatch Repair (MMR) 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 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))