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

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ClinicalTrials.gov Identifier: NCT02633098
Recruitment Status : Recruiting
First Posted : December 17, 2015
Last Update Posted : January 31, 2018
Sponsor:
Information provided by (Responsible Party):
St George's, University of London

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Colorectal Cancer Bowel Cancer Drug: Artesunate 200mg Drug: Placebo Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
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
Actual Study Start Date : April 26, 2017
Estimated Primary Completion Date : February 28, 2019
Estimated Study Completion Date : February 28, 2024

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Artesunate
Artesunate 200mg oral tablets once daily for 14 days.
Drug: Artesunate 200mg
Artesunate 200mg PO OD for 14 days prior to colorectal resection surgery
Placebo Comparator: Matching placebo
Matching placebo oral tablets once daily for 14 days.
Drug: Placebo
Matched placebo PO OD for 14 days prior to colorectal resection surgery



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

Secondary Outcome Measures :
  1. Recurrence free survival at 5 years [ Time Frame: 5 years from study randomisation ]
  2. Overall survival at 2 and 5 years [ Time Frame: 2 and 5 years from study randomisation ]
  3. Colon cancer specific death at 2 and 5 years [ Time Frame: 2 and 5 years from study randomisation ]
  4. 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) ]
  5. 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) ]
  6. 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) ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 6 months following study intervention ]
  11. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 12 months following study intervention ]
  12. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 18 months following study intervention ]
  13. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 24 months following study intervention ]
  14. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 30 months following study intervention ]
  15. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 36 months following study intervention ]
  16. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 42 months following study intervention ]
  17. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 48 months following study intervention ]
  18. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 54 months following study intervention ]
  19. Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Assessment 60 months following study intervention ]
  20. Pathological assessment of tumour regression (involvement of lymph nodes; serosa; resection margin) [ Time Frame: Post surgical pathology review (following Day 14 of study intervention) ]
  21. Patient quality of life [ Time Frame: Assessment at Day 1 of study intervention ]
    Using validated quality of life self-administered questionnaires

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

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

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

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

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

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

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

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

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

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

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

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

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

  35. 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

  36. 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 ]
  37. 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 ]
  38. 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 ]
  39. 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 ]
  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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



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 or high grade dysplasia plus unequivocal radiological evidence of invasive cancer
  3. Stage II/III colorectal cancer planned for 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 10^9 /l; Platelets >100 x 10^9/l; Haemoglobin (Hb) >80g/L
  6. Adequate renal function: Glomerular Filtration Rate >30ml/min by 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 up to 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 the 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 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 to consent is signed until 6 weeks after the last dose of study treatment intervention (i.e. withdrawal, calendar, ovulation, symptothermal and post ovulation methods are not considered acceptable methods)
  4. History of immunosuppression
  5. History of hearing or balance problems
  6. Weight < 52kg or > 110kg
  7. Other planned intervention, apart from standard of care
  8. Any other malignant disease diagnosis within the preceding 2 years with the exception of non-melanomatous skin cancer and carcinoma in situ
  9. Lactose intolerance

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
Kent Oncology Centre, Maidstone Hospital Recruiting
Barming, Kent, United Kingdom, ME16 9QQ
Contact: Mark Dr Hill    01622 225041    mehill@nhs.net   
Contact: Lisa Tribe    01622 227098    ltribe@nhs.net   
Medway Maritime Hospital Not yet recruiting
Gillingham, Kent, United Kingdom, ME7 5NY
Barking, Havering and Redbridge University Hospitals NHS Trust Recruiting
Barking, United Kingdom
Contact: Nirooshun Dr Rajendran    01708 435000 ext 3615    nirooshun.rajendran@bhrhospitals.nhs.uk   
Contact: Alison Ray    01708 435000 ext 3615    alison.ray@bhrhospitals.nhs.uk   
Ashford & St Peters Hospital NHS Foundation Trust Recruiting
Chertsey, United Kingdom
Contact: Pasha Mr Nisar    01932 722318    pasha.nisar@asph.nhs.uk   
Contact: Victoria Frost    01932 723534    victoria.frost@asph.nhs.uk   
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         
Plymouth Hospitals NHS Trust Not yet recruiting
Plymouth, United Kingdom, PL6 8DH
Contact: Clare Miss Adams       clare.adams2@nhs.net   
Contact: Abigail Patrick       abigail.patrick1@nhs.net   
Shrewsbury and Telford Hospital NHS Trust Recruiting
Shrewsbury, United Kingdom
Contact: Jon Mr Lacy-Colson    01743 261000 ext 1460    jon.lacy-colson@sath.nhs.uk   
Contact: Sally Potts    01743 261000 ext 1692      
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

Responsible Party: St George's, University of London
ClinicalTrials.gov Identifier: NCT02633098     History of Changes
Other Study ID Numbers: 15.0154
First Posted: December 17, 2015    Key Record Dates
Last Update Posted: January 31, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

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