A phase I dose-escalation study of the safety and pharmacokinetics of oral Artesunate in patients with advanced hepatocellular carcinoma

Professional info

Location: University Hospital Ghent, Belgium
Collaboration: Professor Hans Van Vlierberghe and Dr. Yves-Paul Vandewynckel

Why did we choose this project?

Hepatocellular carcinoma (HCC), a type of liver cancer, is the second leading cause of cancer-related mortality worldwide, estimated to be responsible for nearly 746,000 deaths per year. The prognosis for HCC is very poor (overall mortality ratio to incidence of 0.95). Conventional chemotherapy is ineffective, and targeted therapy for advanced HCC with the multikinase inhibitor sorafenib shows limited survival benefit (median overall survival 10.7 months vs. 7.9 months).
Artemisinins - compounds extracted from the herb Artemisia annua - are safe and effective FDA-approved antimalarial drugs. Recent studies have suggested that artemisinins also exert anti-angiogenic and cytotoxic effects in human cancer cells. Dihydro-artemisinin, which is the main active metabolite of artemisinins, has been demonstrated to exhibit antitumor effects in various types of human cancers, including liver, lung, breast, ovarian and pancreatic cancer. Artesunate (ART) is a water soluble semisynthetic artemisinin with improved pharmacokinetic properties, and is included in the WHO list as an essential drug for the treatment of malaria. The antitumor and antiangiogenic effects of ART were investigated in a carcinogenic-induced mouse model for HCC. Based on these results, the present phase I dose-escalation trial was designed.

The aim of the project

It was planned to assess the safety of ART and determine the maximum tolerated dose. In addition, the pharmacokinetics of the drug, after oral administration of one dose per day, would have been evaluated. Secondary outcomes included time to tumor progression, quality of life and overall survival.


How did we approach the problem?

Approximately 15 patients were planned to be recruited at the time when the administration of Sorafenib is stopped due to intolerance or therapeutic failure, or when Sorafenib is contraindicated or refused.

What did we find?

This study was terminated due to slow recruitment and expiration of the study drug. In the meantime other trials have opened for the same patient group, including checkpoint inhibitors. This is one of the reasons why this trial was struggling to recruit patients.

Based on the project results, our message to patients:

No conclusions can be made regarding the safety and pharmacokinetics of Artesunate in this patient group. We are happy that other treatment options are being researched in HCC, but regret that this prevented the progress of this project