Safety and Efficacy of Oral Artesunate for Pre-cervical Cancer

Cervical cancer is the fourth most common form of cancer in women globally. It is a significant cause of morbidity and mortality, with over half a million new cases and over 300,000 deaths per year despite being preventable and curable if detected early and managed effectively. Low- and middle-income countries (LMICs) are disproportionately affected, with 80% of cases and 90% of cervical cancer-related deaths occurring in low-resource settings. There is an urgent need to develop affordable therapeutics to manage this global oncology burden. For many women, travel costs, time off work, and childcare responsibilities represent significant barriers to engaging with cervical cancer screening, treatment, and follow-up.

The World Health Organization (WHO) cervical cancer elimination strategy has set a target to eliminate cervical cancer as a public health problem (target incidence \<4/100,000 population). To be on track to achieve this by the end of the century, draft targets include: 90% of girls vaccinated against HPV by the age of 15 years; 70% of all women aged 30 to 49 years receiving at least two high-precision screening tests 10 years apart; and 90% of screen-positive women, as well as 90% of women diagnosed with cervical cancer, receiving treatment by 2030. Countries are called to meet the 90-70-90 targets by 2030 in order to progress toward cervical cancer elimination. It is estimated that over 62 million deaths due to cervical cancer could be prevented in the next 100 years through implementation of this strategy alongside HPV vaccination.

While survival rates from colorectal, breast, prostate, cervical, and lung cancer are improving in high-income countries (HICs) due to a combination of early detection and more effective treatments, cancer death rates in LMICs are increasing. This is in part because many lifesaving cancer treatments remain unaffordable in LMICs, where cancer remains a neglected disease. Novel drug development takes an average of 10-15 years to go from bench to clinic at an average cost of USD 1 billion. Repurposing of established drugs for new indications can shorten this pathway substantially and reduce development costs.

In Malaysia, cervical cancer is the fourth leading cause of cancer-related morbidity and mortality among women, with an annual incidence of 1,700 cases reported in 2018. At present, only approximately 25% of women participate in regular cervical screening, and many patients present with advanced disease, with five-year overall survival around 52%. There is an urgent need for effective, safe, and affordable treatments to improve survival.

Artesunate belongs to the artemisinin family of sesquiterpene trioxane anti-malarial agents derived from Artemisia annua L. (Sweet wormwood), which has been used in traditional Chinese medicine for centuries to treat a variety of conditions including fever, inflammation, and haemorrhage. Artesunate is approved for the treatment of uncomplicated and multidrug-resistant malaria, is listed on the WHO Essential Medicines List, and is available at low cost (approximately USD 1 per daily dose).

Several comprehensive reviews have examined the anticancer effects of artemisinins. Pre-clinical studies in cell lines and animal models have demonstrated broad anticancer activity, including pro-apoptotic, anti-proliferative, anti-angiogenic, and anti-metastatic effects. A Phase I dose-escalation study of artesunate vaginal inserts in biopsy-confirmed cervical intraepithelial neoplasia (CIN) 2/3 in 28 participants demonstrated that treatment was safe and well tolerated, with histologic regression observed in 19 of 28 (67.9%) and HPV viral clearance in 9 of 19 (47.4%) participants. In participants who did not experience histological regression, no viral clearance was observed.

NeoART-CIN is a Phase II clinical study evaluating the safety and effectiveness of oral artesunate in participants with high-grade cervical intraepithelial neoplasia (CIN2/3), with the objective of determining whether a course of oral artesunate can reverse pre-cancerous cervical changes and prevent progression to invasive cancer. Findings from this study will increase scientific understanding of the effects of artesunate on CIN2/3 and may inform future clinical studies.

The primary research objective is to assess the feasibility, safety, and preliminary anti-proliferative activity of oral artesunate in HPV-positive high-grade CIN2/3.

A maximum of 28 participants will be enrolled to receive the study intervention. The primary endpoint is histological regression of CIN2/3, confirmed by colposcopy and biopsy at Day 90. The statistical design tests the null hypothesis that the response rate is 20%, versus the alternative that the response rate is 50%. The significance level is α=0.1, and the power is 90% when the true response rate is 50%. At a significance level of 0.05 and an equivalence margin of 0.15, a sample size of 24 participants is required to achieve 90% power, assuming a historical control response rate of 0.2 and an expected treatment response of 0.5. Accounting for a 20% loss to follow-up, the total sample size is inflated to approximately 28 participants.

Cervical cancer represents significant morbidity and mortality globally, particularly in LMICs. The current standard of care for women with high-grade CIN2/3 includes surgical or ablative treatments. Although these are generally safe, complications such as infection, bleeding, perforation, and cervical stenosis can occur. The most serious late complication is an increased risk of preterm birth and obstetric complications. Even after surgical resection with uninvolved margins, the risk of recurrence may range from 8% to 23%. For many women, barriers such as travel costs, time off work, and childcare continue to impede access to screening, treatment, and follow-up. There is an urgent need to develop safe, effective, and affordable therapeutics that can be delivered at the point of need. An oral treatment that is safe, effective, affordable, and capable of inducing regression of CIN2/3 and HPV clearance would represent a significant advance in the management of this condition.

Trial-specific risks and burdens include additional diagnostic, therapeutic, and monitoring procedures to assess safety, tolerability, and preliminary antiproliferative effects. Participants may not receive direct clinical benefit from participation, but their involvement will contribute to advancing scientific and clinical understanding of artesunate's potential role in treating CIN2/3.

• HPV DNA viral clearance at Day 90. [Срок оценки: Measured at the end of the trial at Day 90]
• Change in Vaginome Composition [Срок оценки: At Day 1 , Day 64 of enrolment and at the end of the trial at Day 90]
• Change in Gut Microbiome Composition Assessed [Срок оценки: At Day 1 , Day 64 of enrolment and at the end of the trial at Day 90]
• Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [Срок оценки: Assessment at Day 90 following study intervention]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires at Baseline [Срок оценки: Assessment at Day 1 of study intervention (baseline)]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires [Срок оценки: Assessment at Day 7 of study intervention]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires [Срок оценки: Assessment at Day 14 of study intervention]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires [Срок оценки: Assessment at Day 22 of study intervention]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires [Срок оценки: Assessment at Day 43 of study intervention]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires [Срок оценки: Assessment at Day 64 of study intervention]
• Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires [Срок оценки: Assessment at Day 90 of study intervention]
• Change in Blood Biomarker Levels Associated with Cervical Intraepithelial Neoplasia (CIN 2/3) [Срок оценки: Day 1, Day 14, Day 64, and Day 90]