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

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.

Sex

All

Minimum age

18 Years

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

• BACKGROUNDKrishna S, Ganapathi S, Ster IC, Saeed ME, Cowan M, Finlayson C, Kovacsevics H, Jansen H, Kremsner PG, Efferth T, Kumar D. A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer. EBioMedicine. 2014 Nov 15;2(1):82-90. doi: 10.1016/j.ebiom.2014.11.010. eCollection 2015 Jan. PMID 26137537
• BACKGROUNDKremsner PG, Krishna S. Antimalarial combinations. Lancet. 2004 Jul 17-23;364(9430):285-94. doi: 10.1016/S0140-6736(04)16680-4. PMID 15262108
• BACKGROUNDKrishna S, Bustamante L, Haynes RK, Staines HM. Artemisinins: their growing importance in medicine. Trends Pharmacol Sci. 2008 Oct;29(10):520-7. doi: 10.1016/j.tips.2008.07.004. Epub 2008 Aug 25. PMID 18752857
• BACKGROUNDSchoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983 Jun;39(2):499-503. PMID 6354290
• BACKGROUNDSingh NP, Panwar VK. Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther. 2006 Dec;5(4):391-4. doi: 10.1177/1534735406295311. PMID 17101767
• BACKGROUNDSteinbruck L, Pereira G, Efferth T. Effects of artesunate on cytokinesis and G(2)/M cell cycle progression of tumour cells and budding yeast. Cancer Genomics Proteomics. 2010 Nov-Dec;7(6):337-46. PMID 21156967
• BACKGROUNDReichert S, Reinboldt V, Hehlgans S, Efferth T, Rodel C, Rodel F. A radiosensitizing effect of artesunate in glioblastoma cells is associated with a diminished expression of the inhibitor of apoptosis protein survivin. Radiother Oncol. 2012 Jun;103(3):394-401. doi: 10.1016/j.radonc.2012.03.018. Epub 2012 May 3. PMID 22560712
• BACKGROUNDNakase I, Lai H, Singh NP, Sasaki T. Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Int J Pharm. 2008 Apr 16;354(1-2):28-33. doi: 10.1016/j.ijpharm.2007.09.003. Epub 2007 Sep 6.