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

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ClinicalTrials.gov Identifier: NCT02304289
Recruitment Status : Completed
First Posted : December 1, 2014
Last Update Posted : January 4, 2017
Sponsor:
Collaborators:
University Ghent
Anticancer Fund, Belgium
Information provided by (Responsible Party):
University Hospital, Ghent

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

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: Artesunate Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Dose-Escalation Study Evaluating the Safety and Pharmacokinetics of Oral Artesunate (ART) in Patients With Advanced Hepatocellular Carcinoma (HCC).
Study Start Date : November 2014
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2016

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




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

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


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02304289


Locations
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Belgium
Dept. of Hepatology & Gastroenterology Ghent University Hospital
Ghent, East-Flandres, Belgium, 9000
Sponsors and Collaborators
University Hospital, Ghent
University Ghent
Anticancer Fund, Belgium
Investigators
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Principal Investigator: Hans Van Vlierberghe, MD, PhD University Ghent
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Responsible Party: University Hospital, Ghent
ClinicalTrials.gov Identifier: NCT02304289    
Other Study ID Numbers: AGO/2014/003
2014-002503-16 ( EudraCT Number )
First Posted: December 1, 2014    Key Record Dates
Last Update Posted: January 4, 2017
Last Verified: January 2017
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Artesunate
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics