HF1K16 is an investigational pegylated liposome formulation of tretinoin for injection 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.

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 HF1K16 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.

Inclusion Criteria:

1. Capable of giving informed consent and complying with study procedures;

2. Between the ages of 18 and 55 years, inclusive;

3. Body mass index (BMI) of 18.0 to 32.0 kg/m2 inclusive and body weight not less than 50 kg;

4. Female subjects must have a negative pregnancy test result at screening and at admission;

5. Female subjects are:

   1. 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)

   2. 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;

6. 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;

7. Considered healthy by the Investigator, based on subject's reported medical history, full physical examination, 12-lead ECG, and vital signs;

8. 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;

9. Non-smoker and has not been exposed to any products containing nicotine in the last 6 months;

10. Willing and able to adhere to study restrictions and to be confined at the Clinical Research Unit

Exclusion Criteria:

1. 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;
2. Known or suspected malignancy;
3. Reported history of pancreatitis or gall stones;
4. Reported history of unexplained syncope, symptomatic hypotension or hypoglycemia;
5. Reported family history of long QTc syndrome or a QTc of > 450 ms at screening;
6. Reported history of chronic diarrhea, malabsorption, unexplained weight loss, food allergies or intolerance;
7. Poor venous access;
8. Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV) at screening;
9. Donated or lost >500 mL of blood in the previous 3 months prior to screening;
10. 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;
11. Taken any prescription medications within 14 days or 5 half-lives (whichever is longer) of the first dose of study drug;
12. 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);
13. Taken daily Vitamin A supplement within 3 months prior to screening;
14. Major surgery or hospitalization within 6 months prior to screening that in the Investigators opinion would put the subject or study conduct at risk;
15. A history of prescription drug abuse, or illicit drug use within 9 months prior to screening;
16. 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;
17. A positive screen for alcohol, drugs of abuse at screening or admission;
18. An unwillingness or inability to comply with food and beverage restrictions during study participation;
19. 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;
20. 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;
21. 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.

Protocol and SAP

six month after completion

public

All AEs (serious and non-serious) were collected from signing the ICF and throughout the study to the follow-up/completion visit. A follow-up telephone call was placed to all subjects on Day 8 (± 2 days) to collect adverse event (AE) and concomitant medication information.