Dose-Escalation Study Evaluating the Safety and Pharmacokinetics of Artesunate in Patients With Hepatocellular Carcinoma (DESPARTH)

October 19, 2021 updated by: University Hospital, Ghent

Phase I Dose-Escalation Study Evaluating the Safety and Pharmacokinetics of Oral Artesunate (ART) in Patients With Advanced Hepatocellular Carcinoma (HCC).

The purpose of this study is to evaluate the Safety and Pharmacokinetics of Oral Artesunate in patients with advanced hepatocellular carcinoma (HCC)

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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 on human cancer cells. Artesunate (ART) is a water soluble semisynthetic artemisinin with improved pharmacokinetic properties.

A single-center phase I dose-escalation study evaluating the safety and pharmacokinetics of oral Artesunate in patients with Advanced HCC.

Approximately 15 patients will be enrolled in this trial. Dose-escalation protocol: The first patient will receive 200 mg Artesunate once-daily for 14 days. If no dose-limiting toxicity (DLT) is observed after 14 days, the next patient will start at a daily dose of 300 mg Artesunate. If no DLT is observed after 14 days, a cohort of 3 patients will receive 400 mg once-daily for 14 days. For each subsequent cohort of 3 patients 200 mg will be added to the dose, until the maximum tolerated dose (MTD) is determined.

Study Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
    • East-Flandres
      • Ghent, East-Flandres, Belgium, 9000
        • Dept. of Hepatology & Gastroenterology Ghent University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically confirmed advanced HCC, based on the report of the department of pathology, excluding fibrolamellar carcinoma.
  • Liver mass measuring at least 2 cm with characteristic vascularization seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium
  • Patients must have refused treatment with sorafenib or must have had treatment with sorafenib, which was either stopped due to intolerance or therapeutic failure.
  • ECOG PS of 0-2.
  • Child Pugh class ≤ B7
  • Life expectancy greater than 3 months in the Investigator's opinion
  • Adequate bone marrow function
  • Adequate hepatic function
  • Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin (β-hCG) or urine pregnancy test at screening. Women who are pregnant or breast feeding are ineligible for this study.
  • For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use adequate methods of contraception (e.g., hormonal implants, combined oral contraceptives, vasectomized partner), during the treatment period and for at least 3 months after the last dose of study treatment
  • For men: agreement to use a barrier method of contraception during the treatment period and for at least 3 months after the last dose of the study treatment.
  • Adequate renal function
  • Each subject (or their legally acceptable representative) must be able and willing to provide an written informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study.
  • Able to swallow capsules
  • Adequate coagulation tests: international normalized ratio (INR) ≤1.5 x ULN
  • Recovery to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies
  • At least 4 weeks since any major surgery or open biopsy and 7 days since a core biopsy before first study treatment
  • The following time must have elapsed between previous therapy for cancer and first administration of ART:
  • At least 2 weeks since previous systemic targeted therapy with small molecule inhibitors, which includes any tyrosine-kinase inhibitor
  • At least 4 weeks since the last dose of systemic anti-cancer therapy other than targeted therapy, which includes cytotoxic agents, monoclonal antibody therapy, immunotherapy and prior radiotherapy

Exclusion Criteria:

  • Patients with Child-Pugh classification > B7
  • Major debilitating disease limiting survival prognosis (incl. heart failure, uncontrolled diabetes, psychiatric disease, hemodialysis, and respiratory insufficiency)
  • Any mental deficiency preventing proper understanding of trial protocol requirements
  • Remaining toxicities from previous sorafenib treatment will be individually evaluated and well documented by the PI.
  • QTc≥440 msec
  • Patients suffering from sinus bradycardia, bradyarrythmia, AV-block I or III.
  • Known allergy to ART or to other artemisinin derivatives
  • Malabsorption or intestinal obstruction
  • History of venous thromboembolic disease within 3 months prior to first administration of study treatment
  • The patient has current, severe and uncontrolled medical condition such as infection, diabetes mellitus or other systemic disease
  • Any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the drug
  • The patient has known positive serology for human immunodeficiency virus
  • Essential medications that are known potent inhibitors or inducers of CYP2B6 and/or CYP3A4
  • Fibrolamellar carcinoma

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Oral Artesunate
The first patient will receive 200 mg Artesunate once-daily for 14 days. If no dose-limiting toxicity (DLT) is observed after 14 days, the next patient will start at a daily dose of 300 mg Artesunate. If no DLT is observed after 14 days, a cohort of 3 patients will receive 400 mg once-daily for 14 days. For each subsequent cohort of 3 patients 200 mg will be added to the dose, until the maximum tolerated dose (MTD) is determined.
Drug: Artesunate
Oral Artesunate once-daily for 14 days, dose-escalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time Frame: 14 days
14 days
Maximum tolerated dose (MTD)
Time Frame: 14 days
14 days
Pharmacokinetic analysis of Cmax, Cmin, Tmax, and AUC.
Time Frame: 2 days
2 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Time to tumor progression (TTP)
Time Frame: Time from the first intake of Artesunate to radiological progression
Time from the first intake of Artesunate to radiological progression
Overall survival (OS)
Time Frame: ime from the first intake of Artesunate to death
ime from the first intake of Artesunate to death
Quality of life based on the "Functional Assessment of Cancer Therapy Hep-30 scale" (FACT-Hep-30)
Time Frame: 14 days
14 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Ghent

Collaborators

University Ghent
Anticancer Fund, Belgium

Investigators

  • Principal Investigator: Hans Van Vlierberghe, MD, PhD, University Ghent

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2014

Primary Completion (Actual)

December 1, 2016

Study Completion (Actual)

December 1, 2016

Study Registration Dates

First Submitted

November 20, 2014

First Submitted That Met QC Criteria

November 25, 2014

First Posted (Estimate)

December 1, 2014

Study Record Updates

Last Update Posted (Actual)

October 27, 2021

Last Update Submitted That Met QC Criteria

October 19, 2021

Last Verified

January 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AGO/2014/003
  • 2014-002503-16 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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