We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Safety and Effectiveness Study of Pre-operative Artesunate in Stage II/III Colorectal Cancer (NeoART)

This study is currently recruiting participants.
Verified October 2017 by St George's, University of London
Sponsor:
ClinicalTrials.gov Identifier:
NCT02633098
First Posted: December 17, 2015
Last Update Posted: October 24, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
St George's, University of London
  Purpose

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 activity of cancer cells.

Two hundred patients diagnosed with 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 returning after treatment.


Condition Intervention Phase
Colorectal Cancer Bowel Cancer Drug: Artesunate 200mg Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II Randomised, Double Blind, Placebo Controlled Trial of Neoadjuvant Artesunate in Stage II/III Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by St George's, University of London:

Primary Outcome Measures:
  • Recurrence free survival at 2 years [ Time Frame: 2 years following study randomisation. ]

Secondary Outcome Measures:
  • Recurrence free survival at 5 years [ Time Frame: 5 years from study randomisation ]
  • Overall survival at 2 and 5 years [ Time Frame: 2 and 5 years from study randomisation ]
  • Colon cancer specific death at 2 and 5 years [ Time Frame: 2 and 5 years from study randomisation ]
  • Number of patients experiencing artesunate drug related toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment at Day 7 following start of study intervention (artesunate/matching placebo) ]
  • Number of patients experiencing artesunate drug related toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment at Day 14 following start of study intervention (artesunate/matching placebo) ]
  • Number of patients experiencing artesunate drug related toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment at Day 42 following start of study intervention (artesunate/matching placebo) ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment at Day 7 following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment at Day 14 following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment at Day 42 following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 6 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 12 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 18 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 24 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 30 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 36 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 42 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 48 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 54 months following study intervention ]
  • Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 60 months following study intervention ]
  • Pathological assessment of tumour regression (involvement of lymph nodes; serosa; resection margin) [ Time Frame: Post surgical pathology review (following Day 14 of study intervention) ]
  • Patient quality of life [ Time Frame: Assessment at Day 1 of study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment at Day 7 of study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment at Day 14 of study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment at Day 42 of study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 6 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 12 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 18 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 24 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 30 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 36 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 42 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 48 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 54 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Patient quality of life [ Time Frame: Assessment 60 months following study intervention ]
    Using validated quality of life self-administered questionnaires

  • Surgical complications [ Time Frame: From time of surgery up to 3 months post surgery ]
    Number of patients with surgery related adverse events as assessed by CTCAE v4.0

  • Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy [ Time Frame: Assessment at Day 1 of study intervention ]
  • Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy [ Time Frame: 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 [ Time Frame: Assessment at Day 14 of study intervention ]
  • Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy [ Time Frame: 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 [ Time Frame: Pre and post intervention tumour samples from patients (Day 0 and Day 15) ]
    Number of patients with Kras mutant tumours

  • Immunohistochemical analyses of paraffin-embedded tumour sections to assess Mismatch Repair (MMR) status [ Time Frame: Pre and post intervention tumour samples from patients (Day 0 and Day 15) ]
    Number of patients with Mismatch Repair (MMR) mutant tumours

  • Immunohistochemical analyses of paraffin-embedded tumour for v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation status [ Time Frame: 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 [ Time Frame: 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 Platelet derived growth factor receptor (PDGFR) expression [ Time Frame: Pre and post intervention tumour samples from patients (Day 0 and Day 15) ]
    Number of patients whose tumours show PDGFR upregulation/downregulation following study intervention

  • Immunohistochemical analyses of paraffin-embedded tumour for Vascular endothelial Growth Factor (VEGF) expression [ Time Frame: 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

  • Immunohistochemical analyses of paraffin-embedded tumour on Vascular endothelial Growth Factor Receptor (VEGFR) expression [ Time Frame: 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

  • Determination of proliferative activity (Ki-67 staining, Cluster of Differentiation 31 protein (CD31) staining) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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

  • Determination of cell-free circulating tumour Deoxyribonucleic acid (ctDNA) levels in patient blood plasma samples [ Time Frame: Pre and post intervention blood samples from patients (Day 0 and Day 15) ]
    Number of patients shown to have an increase or a decrease in cell-free circulating tumour Deoxyribonucleic acid (ctDNA) following study intervention


Estimated Enrollment: 200
Actual Study Start Date: October 3, 2016
Estimated Study Completion Date: May 2023
Estimated Primary Completion Date: October 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Artesunate
Artesunate 200mg oral tablets once daily for 14 days.
Drug: Artesunate 200mg
Placebo Comparator: Matching placebo
Matching placebo oral tablets once daily for 14 days.
Drug: Placebo

Detailed Description:

Artemisinins are a family of sesquiterpene trioxane anti-malarial agents derived from Sweet Wormwood (Artemisia annua L), a plant that has been used in traditional Chinese medicine for centuries. Artesunate is a derivative of artemisinin that is converted into its active metabolite dihydroartemisinin (DHA). Artesunate is a widely used antimalarial with a good safety profile and oral route of administration. Artemisinins have demonstrated broad anti-cancer effects including pro-apoptotic, anti-proliferative, anti-angiogenesis and anti-metastatic effects.

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.

In the NeoART trial, 200 patients with Stage II/III colorectal cancer planned for curative surgery, will be randomly allocated to receive either pre-operative oral artesunate 200mg once daily or matching placebo for two weeks prior to surgery. Patients will be followed up closely for 5 years following treatment to see if artesunate is associated with improved recurrence free survival. The safety and tolerability of neoadjuvant artesunate in colorectal cancer will also be further assessed.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria :

  1. Aged 18 or over
  2. Histologically proven single primary site colorectal adenocarcinoma
  3. Stage II/III colorectal cancer for planned surgical resection and no clinical indication for neoadjuvant preoperative chemotherapy/ chemoradiation therapy
  4. WHO performance status 0,1 or 2
  5. Adequate full blood count: White Cell Count (WCC) >3.0 x 10 /l; Platelets >100 x 10; Haemoglobin (Hb) >8g/dL
  6. Adequate renal function: Glomerular Filtration Rate >30ml/min by Wright/Cockcroft-Gault formula
  7. Adequate hepatobiliary function: Bilirubin < 3 x Upper limit normal
  8. Female participants of child bearing 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 intervention.
  9. Male participants with a partner of childbearing potential must agree to use adequate, medically approved contraceptive precautions during and for 6 weeks after the last dose of the study treatment intervention
  10. Patient able and willing to provide written, informed consent for the study

Exclusion criteria:

  1. Contraindication to use of artesunate due to hypersensitivity
  2. Pregnancy or lactation
  3. 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 (i.e. withdrawal, calendar, ovulation, symptothermal and post ovulation are not acceptable methods) from time consent is signed until 6 weeks after the last dose of study treatment intervention
  4. History of immunosuppression, hearing or balance problems
  5. Weight < 52 kg or > 110 kg
  6. Other planned intervention, apart from standard of care
  7. Any other malignant disease diagnosis within the preceding 2 years with the exception of non-melanomatous skin cancer and carcinoma in situ
  8. Lactose intolerance
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02633098


Contacts
Contact: Professor Sanjeev Krishna, FRCP, ScD, FMedSci ++44(0)208 725 5836 s.krishna@sgul.ac.uk
Contact: Dr Yolanda Augustin, MBBS, MRCP, FRCR, MSc ++44(0)2087255722 yaugusti@sgul.ac.uk

Locations
United Kingdom
St George's University Hospitals NHS Fundation Trust Recruiting
London, United Kingdom, SW17 0RE
Contact: Yolanda Augustin, MBBS, MRCP,MSc, FRCR    02087255722    yaugusti@sgul.ac.uk   
Principal Investigator: Andrew Rawmell, MA, MD, FRCS         
Sponsors and Collaborators
St George's, University of London
Investigators
Principal Investigator: Professor Devinder Kumar, MBBS, PhD, FRCS St George's University Hospitals NHS Foundation Trust
  More Information

Responsible Party: St George's, University of London
ClinicalTrials.gov Identifier: NCT02633098     History of Changes
Other Study ID Numbers: 15.0154
First Submitted: November 18, 2015
First Posted: December 17, 2015
Last Update Posted: October 24, 2017
Last Verified: October 2017

Keywords provided by St George's, University of London:
Artesunate
Artemisinins
Antimalarial
Neoadjuvant
Pre-operative

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Artesunate
Artemisinins
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials