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

Official title

Phase II Randomised, Double Blind, Placebo Controlled Trial of Neoadjuvant Artesunate in Stage II/III Colorectal Cancer

Overview

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

• Drug Artesunate
  Artesunate 200mg PO OD for 14 days prior to colorectal resection surgery
• Drug Artesunate matching Placebo
  Matched placebo PO OD for 14 days prior to colorectal resection surgery

Primary outcome measures

• Recurrence-Free Survival (RFS) at 2 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation [Time frame: 2 years following study randomisation.]

Secondary outcome measures (12)

• Recurrence-Free Survival at 5 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation [Time frame: 5 years from study randomisation]
• Overall Survival (OS) at 2 and 5 Years Post-Randomisation [Time frame: 2 years and 5 years following study randomisation.]
• Colon Cancer-Specific Mortality at 2 and 5 Years Post-Randomisation [Time frame: 2 years and 5 years following study randomisation.]
• Incidence of Artesunate-Related Toxicity Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [Time frame: Assessment at Day 7 following initiation of study intervention (artesunate or matching placebo).]
• Incidence of Artesunate-Related Toxicity Assessed by Common Terminology CTCAE v5.0 [Time frame: Assessment at Day 14 following initiation of study intervention (artesunate or matching placebo).]
• Incidence of Artesunate-Related Toxicity Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [Time frame: Assessment at Day 42 following initiation of study intervention (artesunate or matching placebo).]
• Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [Time frame: 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 [Time frame: 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 [Time frame: Assessment at Day 42 following study intervention]
• Pathological assessment of tumour regression post intervention [Time frame: Post surgical pathology review (following Day 14 of study intervention)]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires at Baseline [Time frame: Assessment at Day 1 of study intervention (baseline assessment)]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires [Time frame: Assessment at Day 7 of study intervention]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Malaysia · 6 centers

• Hospital Sultanah Bahiyah — Alor Star
• Hospital Kuala Lumpur — Kuala Lumpur
• Pusat Perubatan Universiti Malaya — Kuala Lumpur
• Hospital Umum Sarawak — Kuching
• Hospital Sungai Buloh — Sungai Buloh
• Hospital Pulau Pinang — Pulau Pinang

Publications

• Krishna 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
• Kremsner PG, Krishna S. Antimalarial combinations. Lancet. 2004 Jul 17-23;364(9430):285-94. doi: 10.1016/S0140-6736(04)16680-4. PMID 15262108
• Krishna 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
• Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983 Jun;39(2):499-503. PMID 6354290
• Singh 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
• Steinbruck 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
• Reichert 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
• Nakase 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. PMID 17942255

Identifiers

NCT: NCT07095309 · 2023-MHL-001 · NMRR ID-24-01879-TSI

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗