A Phase I Clinical Study on a New Oral Pentamidine Formulation in Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to investigate on the Hepatic Uptake, Pharmacokinetics, Safety and Tolerance of a New Oral Pentamidine Formulation in Hepatocellular Carcinoma Subjects Undergoing Thermal Ablation

Detailed Description
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This is a Phase 1, randomized, double-blind, placebo-controlled, sequential-group administration of a new oral pentamidine formulation to investigate its hepatic uptake, pharmacokinetics, safety and tolerance in subjects with hepatocellular carcinoma who undergoes thermal ablation procedure

Official Title
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A Phase I Clinical Study on the Hepatic Uptake, Pharmacokinetics, Safety and Tolerance of a New Oral Pentamidine Formulation in Hepatocellular Carcinoma Subjects Undergoing Thermal Ablation

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Oral Pentamidine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 18 years of age or older Radiologically established diagnosis of hepatocellular carcinoma (HCC) with tumor diameter ≤ 5 cm Suitable for and scheduled to undergo thermal ablation as treatment Have a Barcelona score of 0 or A Have a Child Pugh score of A or B Legally and mentally able to give informed consent to participate in the study Signature of a dated Informed Consent Form (ICF) indicating that the subject has been informed of all the relevant aspects of the trial prior to enrolment Willingness and ability to comply with scheduled visits and trial procedures Exclusion Criteria: Presence of uncontrolled diabetes, defined as glycated hemoglobin (Hb1Ac) ≥ 8.0 History of clinically significant hypoglycaemia, with fasting blood glucose < 3 mmol/L within 3 months prior to signature of ICF Presence of clinically significant renal impairment, defined as a creatinine clearance < 60 mL/min Systolic Blood Pressure < 100 mm Hg (if deemed clinically significant by the treating physician) Current or recent (< 2 years) history of pancreatitis International Normalised Ratio (INR) > 1.5 or presence of severe coagulation disorders (vg but limited to prothrombin activity < 40% or a platelet count of < 40,000 / mm3) Presence of known vascular invasion, bile duct invasion or extrahepatic metastasis Presence of portal venous thrombosis Concomitant therapy with other investigational agents or participation in another clinical trial within 3 months of signature of ICF Previous use of pentamidine with treatment discontinuation of less than 6 months prior to signature of ICF Any of the following conditions: Ongoing clinically significant cardiac dysrhythmias such as atrial fibrillation ; QTc interval > 450 msec for males or > 470 msec for females or uncontrolled intercurrent cardiac illness, e.g. unstable angina; severe coronary disease, ventricular arrhythmias, bradycardia < 50 bpm (unless caused by beta-blocker); a history of additional risk factors for torsades de pointes (e.g., heart failure or family history of Long QTC Syndrome) Presence of clinically significant hypokalemia or hypomagnesemia Concurrent use of nephrotoxic drugs Concurrent use of cardiotoxic drugs Concurrent use of drugs that may be associated with pancreatitis History of allergy or hypersensitivity to pentamidine Pregnancy or breastfeeding. All female subjects of childbearing potential must have a negative urine pregnancy test prior to first dose of study medication. Acute or chronic severe medical or psychiatric condition, or laboratory abnormality that would impart, in the judgement of the investigator, excess risk associated with trial participation of study drug administration, or which in the judgement of the investigator, would make the subject inappropriate for entry into this trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral pentamidine<br>Oral pentamidine given at 300 mg, 600 mg, 900 mg or 1200 mg QD x 3 consecutive days | Drug: Oral Pentamidine<br>* Oral pentamidine given at 300 mg, 600 mg, 900 mg or 1200 mg QD x 3 consecutive days<br>* Other names: VLX103;|
| Placebo Comparator: Placebo<br>Placebo given at 300 mg, 600 mg, 900 mg or 1200 mg QD x 3 consecutive days | Other: Placebo<br>* Placebo given at 300 mg, 600 mg, 900 mg or 1200 mg QD x 3 consecutive days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pharmacokinetics | Liver concentration of pentamidine in hepatocellular carcinoma tumor and surrounding tissue after oral administration for 3 days at different doses, measured in liver biopsies obtained during thermal ablation procedure | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma Pharmacokinetics | Plasma concentration of pentamidine after oral administration for 3 days at different doses | 3 days | 
| Adverse events | Safety as assessed by adverse events (AE), vital signs and laboratory parameters | 3 days | 
| markers of efficacy | The levels of Plasma pharmacodynamic markers of efficacy: ALT and AST | 3 days | 
| Biomarker | Tissue biomarker of mechanism of action: Endo-exonuclease | 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular carcinoma, Oral Pentamidine, Endo-exonuclease