Evaluate the Safety, Tolerability and PK of HF1K16 in Healthy Volunteers

Study Overview
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Brief Summary
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HF1K16 is an investigational pegylated liposome formulation of tretinoin for injection for the induction of remission in patients with acute promyelocytic leukemia (APL) and for the treatment of solid tumors through targeting myeloid derived suppressor cells (MDSCs). This phase 1 Trial is a Randomized, Double-Blind, Placebo-Controlled Study in Healthy Subjects to Evaluate the Safety, Tolerability and Pharmacokinetics of HF1K16.

Detailed Description
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Tretinoin is a naturally occurring vitamin A metabolite that participates in many biological processes. It is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells achieving complete remission (CR). In addition, ATRA and similar retinoids were also discovered to have significant immune-modulating activities towards Myeloid derived suppressor cells (MDSCs) that contribute greatly to cancer growth and progression. Preclinical efficacies of ATRA to induce MDSC differentiation into dendritic cells (DCs) and downregulate their inhibitory effects on cytotoxic T cell activities against cancer have been demonstrated. HF1K16 is a pegylated liposome formulation of tretinoin developed for improved PK behavior, higher therapeutic index, and more specific targeted mechanism towards MDSCs. The objectives of this study are to assess the safety and tolerability of HF1K16. The ATRA pharmacokinetic parameters will be determined with correlations to the liposome doses administered.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study Following Intravenous Administration of HF1K16 in Healthy Subjects to Evaluate the Safety, Tolerability and Pharmacokinetics of HF1K16

Conditions
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Healthy

Intervention / Treatment
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* Drug: HF1K16
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving informed consent and complying with study procedures; Between the ages of 18 and 55 years, inclusive; Body mass index (BMI) of 18.0 to 32.0 kg/m2 inclusive and body weight not less than 50 kg; Female subjects must have a negative pregnancy test result at screening and at admission; Female subjects are: Surgically sterile for at least 3 months prior to screening by one of the following means: Bilateral tubal ligation Bilateral salpingectomy (with or without oophorectomy) Surgical hysterectomy Bilateral oophorectomy (with or without hysterectomy) Postmenopausal, defined as the following: Last menstrual period greater than 12 months prior to screening, and Postmenopausal status confirmed by serum follicle stimulating hormone (FSH) and estradiol levels at screening; Male subjects must agree to utilize a highly effective method of contraception (condom plus spermicide) during heterosexual intercourse from the time of clinic admission until 12 weeks following the end of study visit, and refrain from donating sperm for this same period; Considered healthy by the Investigator, based on subject's reported medical history, full physical examination, 12-lead ECG, and vital signs; Have clinical laboratory renal (eGFR, creatinine) and liver (AST, ALT, Total bilirubin) function within normal range and other clinical laboratory results within normal range or outside normal range assessed as clinically non-significant by the Investigator at screening and admission; Non-smoker and has not been exposed to any products containing nicotine in the last 6 months; Willing and able to adhere to study restrictions and to be confined at the Clinical Research Unit Exclusion Criteria: Clinically significant reported history of gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, or drug hypersensitivity as determined by the Investigator; Known or suspected malignancy; Reported history of pancreatitis or gall stones; Reported history of unexplained syncope, symptomatic hypotension or hypoglycemia; Reported family history of long QTc syndrome or a QTc of > 450 ms at screening; Reported history of chronic diarrhea, malabsorption, unexplained weight loss, food allergies or intolerance; Poor venous access; Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV) at screening; Donated or lost >500 mL of blood in the previous 3 months prior to screening; Taken an investigational drug or participated in a clinical trial within 30 days (or 5 half-lives) prior to first dose of study drug, whichever is longer; Taken any prescription medications within 14 days or 5 half-lives (whichever is longer) of the first dose of study drug; Taken any prescription or non-prescription drugs and herbal medication known to be CYP450 inducers, inhibitors, and substrates within 14 days prior to screening (See Appendix B); Taken daily Vitamin A supplement within 3 months prior to screening; Major surgery or hospitalization within 6 months prior to screening that in the Investigators opinion would put the subject or study conduct at risk; A history of prescription drug abuse, or illicit drug use within 9 months prior to screening; A history of alcohol abuse according to medical history (≥ 2 drinks per day for male and ≥ 1 drink per day for female) within 9 months prior to screening; A positive screen for alcohol, drugs of abuse at screening or admission; An unwillingness or inability to comply with food and beverage restrictions during study participation; Use of over-the-counter (OTC) medication within 7 days, and/or herbal medications (including herbal teas, garlic extracts) within 7 days prior to first dose of study drug; Have a history of allergic reactions (either spontaneous or following drug administration) to ATRA or to any of the excipients or related compounds, including vitamin A; Any condition or finding that in the Investigators opinion would put the subject or study conduct at risk if the subject were to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HF1K16<br>Up 32 subjects, comprised of up to 4 cohorts of 8 subjects each, will receive a single IV dose of study drug. Six of the 8 subjects in each cohort will receive HF1K16 and 2 subjects will receive placebo in a blinded manner Cohort 1: up to 3 mg/m2 of HF1K16 or placebo Cohort 2: up to 6 mg/m2 of HF1K16 or placebo Cohort 3: up to 10 mg/m2 of HF1K16 or placebo Cohort 4: up to 13 mg/m2 of HF1K16 or placebo | Drug: HF1K16<br>* A range of doses of HF1K16 will be tested based on the assessment of safety, tolerability and pharmacokinetics.<br>* Other names: ATRA Injection;|
| Placebo Comparator: Placebo<br>Up 32 subjects, comprised of up to 4 cohorts of 8 subjects each, will receive a single IV dose of study drug. Six of the 8 subjects in each cohort will receive HF1K16 and 2 subjects will receive placebo in a blinded manner Cohort 1: up to 3 mg/m2 of HF1K16 or placebo Cohort 2: up to 6 mg/m2 of HF1K16 or placebo Cohort 3: up to 10 mg/m2 of HF1K16 or placebo Cohort 4: up to 13 mg/m2 of HF1K16 or placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of HF1K16 by AE | Incidence of Adverse Events | up to 8 days after treatment | 
| To evaluate the safety and tolerability of HF1K16 by ECG from ventricular rate | changes of ventricular rate in bpm per minute | up to 8 days after treatment | 
| To evaluate the safety and tolerability of HF1K16 by respiration rate of vital signs | Changes from baseline for respiration rate in breaths per minute | Up to 8 Days | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Red blood cell count | Changes from baseline for Red blood cell count in 10^12 /L in whole blood | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by ECG from QRS Duration | Changes from baseline for QRS duration in msec before and after using HF1K16 | up to 8 days after treatment | 
| To evaluate the safety and tolerability of HF1K16 by ECG from QT Interval | Changes from baseline for QT interval in msec before and after using HF1K16. | up to 8 days after treatment | 
| To evaluate the safety and tolerability of HF1K16 by ECG from QTc Interval | Changes from baseline for QTc interval in msec before and after using HF1K16. | up to 8 days after treatment | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Red blood cell count in whole blood | Changes from baseline for Red blood cell count in 10^12 /L in whole blood | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Changes from White blood cell count in whole blood | Changes from baseline for white blood cell count in 10^9 /L in whole blood | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Neutrophil count in whole blood | Changes from baseline for neutrophil count in 10^9/L in whole blood | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Hemoglobin concentration in whole blood | Changes from baseline for hemoglobin concentration in g/dL | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Prothrombin time | Changes from baseline for Prothrombin time in s | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by International standardized ratio | Changes from baseline for international standardized ratio | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from International sensitivity index | Changes from baseline for international sensitivity index | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Activated partial thromboplastin time | Changes from baseline for activated partial thromboplastin time in s | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Total bilirubin concentration | Changes from baseline for total bilirubin concentration in μmol/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from ALT concentration | Changes from baseline for ALT concentration in U/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from AST concentration | Changes from baseline for AST concentration in U/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Total protein concentration | Changes from baseline for total protein concentration in g/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Urea concentration | Changes from baseline for urea concentration in mmol/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Creatinine concentration | Changes from baseline for creatinine concentration in μmol/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Total cholesterol concentration | Changes from baseline for total cholesterol concentration in mmol/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from Triglycerides concentration | Changes from baseline for triglycerides concentration in mmol/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from HDL-C | Changes from baseline for HDL-C in mmol/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by Laboratory Examination from LDL-C | Changes from baseline for LDL-C in mmol/L | within 21 days after administration | 
| To evaluate the safety and tolerability of HF1K16 by heart rate of vital signs | Changes from baseline for heart rate in beats per minute | Up to 8 Days | 
| To evaluate the safety and tolerability of HF1K16 by blood pressure of vital signs | Changes from baseline for blood pressure in mmHg | Up to 8 Days | 
| To evaluate the safety and tolerability of HF1K16 by body temperature of vital signs | Changes from baseline for body temperature in Celsius degree | Up to 8 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the pharmacokinetics with MRT | Mean Residence Time(MRT) of HF1K16 | Up to 48 hours postdose | 
| To characterize the pharmacokinetics with Maximum plasma concentration | maximum plasma concentration (Cmax) of HF1K16 | Up to 48 hours postdose | 
| To characterize the pharmacokinetics of with AUC0-inf | Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) of HF1K16 | Up to 48 hours postdose | 
| To characterize the pharmacokinetics with with AUC0-48 | Area under the plasma concentration-time curve from time 0 to 48hr(AUC00-48hr) of HF1K16 | Up to 48 hours postdose | 
| To characterize the pharmacokinetics with Tmax | Time of maximum concentration (Tmax) of HF1K16 | Up to 48 hours postdose | 
| To characterize the pharmacokinetics with T1/2 | Elimination half-life (T1/2) of HF1K16 | Up to 48 hours postdose | 
| To characterize the pharmacokinetics with CL/F | Descriptive statistics of CL/F (Apparent total body clearance of drug from plasma after dose of HF1K16) | Up to 48 hours postdose | 
| To characterize the pharmacokinetics with VzF | Descriptive statistics of Vz/F (Apparent volume of distribution during the terminal phase after dose of HF1K16) | Up to 48 hours postdose |