Bowel Cancer, Stage II/III Colon Cancer
Conditions
Keywords
artesunate, colorectal, drug repurposing, antimalarial
Brief summary
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.
Detailed description
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.
Interventions
DRUGArtesunate
Artesunate 200mg PO OD for 14 days prior to colorectal resection surgery
DRUGArtesunate matching Placebo
Matched placebo PO OD for 14 days prior to colorectal resection surgery
Sponsors
Clinical Research Malaysia
Metanoic Health Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a Phase II randomised, placebo-controlled, double-blind trial of neoadjuvant oral artesunate 200 mg once daily for 14 days in patients with histologically confirmed colorectal cancer (CRC) Stage II/III awaiting surgical treatment with curative intent. The study null hypothesis is that there is no difference in survival outcomes between patients with Stage II/III colorectal cancer who receive neoadjuvant artesunate 200 mg once daily for 14 days prior to surgery and those receiving a matching placebo tablet. A randomised, placebo-controlled, double-blind design has been chosen to minimise potential researcher bias. A placebo arm is included as there is currently no standard neoadjuvant treatment in Stage II/III colon cancer.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-Free Survival (RFS) at 2 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) at 2 and 5 Years Post-Randomisation | 2 years and 5 years following study randomisation. | Survival status will be determined through clinical follow-up, hospital records, and national death registries where available. Unit of Measure: Months |
| Colon Cancer-Specific Mortality 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 7 following initiation of study intervention (artesunate or matching placebo). | The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one artesunate-related adverse event, by CTCAE grade. |
| 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). | The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Causality will be assessed by the site investigator and confirmed by the clinical trial safety team. Adverse events will be coded and reported by type and severity. |
| 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). | The number and proportion of participants experiencing any adverse events (AEs), regardless of causality, will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one adverse event, categorised by CTCAE grade. |
| 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 | The number and proportion of participants experiencing any adverse events (AEs), regardless of causality, will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one adverse event, categorised by CTCAE grade. |
| 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 | The number and proportion of participants experiencing any adverse events (AEs), regardless of causality, will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one adverse event, categorised by CTCAE grade. |
| Pathological assessment of tumour regression post intervention | Post surgical pathology review (following Day 14 of study intervention) | Tumour regression will be assessed by histopathological examination of the surgical resection specimen. The assessment will include: * Degree of tumour regression in the primary tumour bed * Presence of tumour involvement at the resection margins * Evidence of tumour invasion into the serosa (pT4a) and lymph node involvement (number and proportion of positive lymph nodes). * Histopathological evaluation Unit of Measure: Number and proportion of participants with positive lymph nodes, serosal involvement, and positive resection margins. |
| 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) | Number of patients whose tumours show VEGFR upregulation/downregulation following study intervention |
| Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires at Baseline | Assessment at Day 1 of study intervention (baseline assessment) | Quality of life will be assessed using validated, self-administered questionnaires: 1. EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) 2. EORTC QLQ-CR29 (Colorectal Cancer-Specific Module) These instruments evaluate global health status/QoL, functional scales (physical, role, emotional, cognitive, social), and symptom scales. Scores for each scale range from 0 to 100. For functional and global health status scales, higher scores indicate better QoL. For symptom scales, higher scores indicate worse symptoms. Unit of Measure: Mean scores for each scale/domain of the EORTC QLQ-C30 and QLQ-CR29 questionnaires. |
| Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires | Assessment at Day 7 of study intervention | Quality of life will be assessed using validated, self-administered questionnaires: 1. EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) 2. EORTC QLQ-CR29 (Colorectal Cancer-Specific Module) These instruments evaluate global health status/QoL, functional scales (physical, role, emotional, cognitive, social), and symptom scales. Scores for each scale range from 0 to 100. For functional and global health status scales, higher scores indicate better QoL. For symptom scales, higher scores indicate worse symptoms. Unit of Measure: Mean scores for each scale/domain of the EORTC QLQ-C30 and QLQ-CR29 questionnaires. |
| Recurrence-Free Survival at 5 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation | 5 years from 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 CEA . Histological confirmation of recurrence will be obtained where clinically indicated. Unit of Measure: Months |
| Incidence of Surgery-Related Adverse Events Assessed by CTCAE v5.0 | From time of surgery up to 3 months post surgery | The number and proportion of participants experiencing surgery-related adverse events (AEs) will be recorded. Events will be graded using the CTCAE version 5.0, with severity classified from Grade 1 (mild) to Grade 5 (death related to AE). Events of interest include, but are not limited to, surgical site infection, anastomotic leak, wound dehiscence, postoperative bleeding, and thromboembolic events. Unit of Measure: Number of participants with at least one surgery-related AE, categorised by CTCAE grade. |
| Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy | Day 1 of study intervention (baseline assessment). | Carcinoembryonic Antigen (CEA) levels will be measured in blood samples and their predictive value for response to artesunate therapy. he predictive value will be evaluated by correlating CEA with pathological tumour regression grade and recurrence-free survival. Unit of Measure: Change in serum CEA levels (ng/mL) |
| 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) | KRAS mutation status will be assessed in tumour tissue sections obtained from pre-intervention (diagnostic biopsy, Day 0) and post-intervention (surgical resection, Day 15) samples. Immunohistochemistry (IHC) will be performed. Comparisons will be made to evaluate changes in mutation status and association with response to artesunate therapy. Unit of Measure: Number and proportion (%) of participants with KRAS mutant tumours at each time point. |
| 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) | Mismatch Repair (MMR) status will be assessed in tumour tissue sections obtained from pre-intervention (diagnostic biopsy, Day 0) and post-intervention (surgical resection, Day 15) samples. Immunohistochemistry (IHC) will be performed. Unit of Measure: Number and proportion (%) of participants with MMR-deficient tumours at each time p |
| 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) | Number of patients with BRAF mutant tumours |
| 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) | Number of patients whose tumours show PDGF upregulation/downregulation following treatment intervention |
| 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) | Number of patients whose tumours show VEGF upregulation/downregulation following study intervention |
| 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) | Number of patients whose tumours show an increase or reduction in proliferation markers Ki67 and CD31 following study intervention |
| Determination of activation of the Deoxyribonucleic acid damage response (DDR) pathway | Pre and post intervention tumour samples from patients (Day 0 and Day 15) | Number of patients whose tumour samples show activation of the DDR pathway following study intervention |
| 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) | Number of patients who show an increase or a decrease in expression of proteins involved in the Wnt/β-catenin proliferation pathway (e.g. c-myc and cyclinD1 proteins) following study intervention |
| Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires post intervention | Assessment at Day 14 of study intervention | Quality of life will be assessed using validated, self-administered questionnaires: 1. EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) 2. EORTC QLQ-CR29 (Colorectal Cancer-Specific Module) These instruments evaluate global health status/QoL, functional scales (physical, role, emotional, cognitive, social), and symptom scales. Scores for each scale range from 0 to 100. For functional and global health status scales, higher scores indicate better QoL. For symptom scales, higher scores indicate worse symptoms. Unit of Measure: Mean scores for each scale/domain of the EORTC QLQ-C30 and QLQ-CR29 questionnaires. |
Countries
Malaysia
Contacts
Primary ContactDr Yolanda Augustin
Backup ContactDr Nafeesa Mat Ali
Outcome results
None listed