Healthy
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGHF1K16
HF1K16 for Injection doses will be calculated based on subject weight measured at admission, and diluted in sterile saline (0.9% sodium chloride). Doses will be administered using an IV infusion pump over a period of approximately 60 minutes at 2.5 mL/min.
DRUGPlacebo
Placebo will be sterile saline (0.9% sodium chloride) which will be administered using an IV infusion pump over a period of approximately 60 minutes at 2.5 mL/min.
Sponsors
HighField Biopharmaceuticals Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE) | from Day 1 to Day 8 | Safety evaluation within 8 days after first dose, including frequency of adverse event (AE) and severe adverse event (SAE) |
| Number of Participants With Dose-Limiting Toxicities (DLTs) | from Day 1 to Day 8 | DLT is defined as Specify that any one grade ≥ 3 AE will halt dose escalation unless the AE is clearly and incontrovertibly due to extraneous causes; Specify that any two grade ≥ 2 AEs will halt dose escalation unless the AEs are clearly and incontrovertibly due to extraneous causes；Grade 3 asymptomatic laboratory abnormalities that resolved to ≤ grade 1 within 3 days may be excluded from the definition of DLT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Drug Concentration (Cmax) After Single Dose of HF1K16 | pre-infusion (within 60 minutes prior to the start of infusion) and 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, and 48 hours relative to start of infusion | To evaluate pharmacokinetic parameters of free tretinoin and liposome encapsulated tretinoin (4-oxotretinoin) in plasma after single administration of HF1K16 |
| A Summary of Pharmacokinetic Parameters (AUC0-t) After Single Dose of HF1K16 | pre-infusion (within 60 minutes prior to the start of infusion) and 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, and 48 hours relative to start of infusion | To evaluate pharmacokinetic parameters of free tretinoin and liposome encapsulated tretinoin (4-oxotretinoin) in plasma after single administration of HF1K16 |
| A Summary of Pharmacokinetic Parameters (Tmax) After Single Dose of HF1K16 | pre-infusion (within 60 minutes prior to the start of infusion) and 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, and 48 hours relative to start of infusion | o evaluate pharmacokinetic parameters of free tretinoin and liposome encapsulated tretinoin (4-oxotretinoin) in plasma after single administration of HF1K16 |
Countries
United States
Participant flow
Recruitment details
Sixteen subjects were enrolled and randomized to receive active study drug or placebo. All subjects were recruited in medical clinic,Frontage Clinical Services, Inc. started on 20March2021 till 28July2021.
Participants by arm
| Arm | Count |
|---|---|
| 3 mg/m² HF1K16 6 subjects received 3 mg/m² of HF1K16 | 6 |
| Placebo 4 subjects received placebo. | 4 |
| 6 mg/m² HF1K16 6 subjects received 6 mg/m² of HF1K16 | 6 |
| Total | 16 |
Baseline characteristics
| Characteristic | 3 mg/m² HF1K16 | Placebo | 6 mg/m² HF1K16 | Total |
|---|---|---|---|---|
| age | 37.3 years | 47.3 years | 40 years | 40.8 years |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 4 Participants | 6 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Sex/Gender, Customized Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex/Gender, Customized Male | 6 Participants | 4 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 4 |
| other Total, other adverse events | 0 / 6 | 4 / 6 | 0 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 4 |
Outcome results
Primary
Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE)
Safety evaluation within 8 days after first dose, including frequency of adverse event (AE) and severe adverse event (SAE)
Time frame: from Day 1 to Day 8
Population: The analysis population included all participants who exposure to study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE) | Number of AEs | 0 participants |
| Placebo | Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE) | Subjects with SAE | 0 participants |
| HF1K16-3mg/m² | Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE) | Number of AEs | 0 participants |
| HF1K16-3mg/m² | Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE) | Subjects with SAE | 0 participants |
| HF1K16-6mg/m² | Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE) | Number of AEs | 4 participants |
| HF1K16-6mg/m² | Number of Participants With Adverse Event (AE) and Severe Adverse Event (SAE) | Subjects with SAE | 0 participants |
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs)
DLT is defined as Specify that any one grade ≥ 3 AE will halt dose escalation unless the AE is clearly and incontrovertibly due to extraneous causes; Specify that any two grade ≥ 2 AEs will halt dose escalation unless the AEs are clearly and incontrovertibly due to extraneous causes；Grade 3 asymptomatic laboratory abnormalities that resolved to ≤ grade 1 within 3 days may be excluded from the definition of DLT
Time frame: from Day 1 to Day 8
Population: Analysis population includes all participants who received at least one dose of HF1K16 and completed safety follow-up through the DLT evaluation period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 participants |
| HF1K16-3mg/m² | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 participants |
Secondary
A Summary of Pharmacokinetic Parameters (AUC0-t) After Single Dose of HF1K16
To evaluate pharmacokinetic parameters of free tretinoin and liposome encapsulated tretinoin (4-oxotretinoin) in plasma after single administration of HF1K16
Time frame: pre-infusion (within 60 minutes prior to the start of infusion) and 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, and 48 hours relative to start of infusion
Population: The PK analysis population included all participants who were compliant with the study procedures and provided sufficient plasma concentrations of tretinoin and 4-oxotretinoin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | A Summary of Pharmacokinetic Parameters (AUC0-t) After Single Dose of HF1K16 | AUC(0-last ) of tretinoin | 469 h*ng/mL | Standard Deviation 93.3 |
| Placebo | A Summary of Pharmacokinetic Parameters (AUC0-t) After Single Dose of HF1K16 | AUC(0-last ) of 4-oxotretinoin | 2.58 h*ng/mL | Standard Deviation 1.78 |
| HF1K16-3mg/m² | A Summary of Pharmacokinetic Parameters (AUC0-t) After Single Dose of HF1K16 | AUC(0-last ) of tretinoin | 810 h*ng/mL | Standard Deviation 113 |
| HF1K16-3mg/m² | A Summary of Pharmacokinetic Parameters (AUC0-t) After Single Dose of HF1K16 | AUC(0-last ) of 4-oxotretinoin | 9.24 h*ng/mL | Standard Deviation 3.21 |
Secondary
A Summary of Pharmacokinetic Parameters (Tmax) After Single Dose of HF1K16
o evaluate pharmacokinetic parameters of free tretinoin and liposome encapsulated tretinoin (4-oxotretinoin) in plasma after single administration of HF1K16
Time frame: pre-infusion (within 60 minutes prior to the start of infusion) and 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, and 48 hours relative to start of infusion
Population: The PK analysis population included all participants who were compliant with the study procedures and provided sufficient plasma concentrations of tretinoin and 4-oxotretinoin
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | A Summary of Pharmacokinetic Parameters (Tmax) After Single Dose of HF1K16 | Tmax of tretinoin | 0.92 h |
| Placebo | A Summary of Pharmacokinetic Parameters (Tmax) After Single Dose of HF1K16 | Tmax of 4-oxotretinoin | 1.5 h |
| HF1K16-3mg/m² | A Summary of Pharmacokinetic Parameters (Tmax) After Single Dose of HF1K16 | Tmax of tretinoin | 0.92 h |
| HF1K16-3mg/m² | A Summary of Pharmacokinetic Parameters (Tmax) After Single Dose of HF1K16 | Tmax of 4-oxotretinoin | 1.8 h |
Secondary
Peak Drug Concentration (Cmax) After Single Dose of HF1K16
To evaluate pharmacokinetic parameters of free tretinoin and liposome encapsulated tretinoin (4-oxotretinoin) in plasma after single administration of HF1K16
Time frame: pre-infusion (within 60 minutes prior to the start of infusion) and 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, and 48 hours relative to start of infusion
Population: The PK analysis population included all participants who were compliant with the study procedures and provided sufficient plasma concentrations of tretinoin and 4-oxotretinoin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Peak Drug Concentration (Cmax) After Single Dose of HF1K16 | Cmax of tretinoin | 198 ng/mL | Standard Deviation 45.6 |
| Placebo | Peak Drug Concentration (Cmax) After Single Dose of HF1K16 | Cmax of 4-oxotretinoin | 3.14 ng/mL | Standard Deviation 0.902 |
| HF1K16-3mg/m² | Peak Drug Concentration (Cmax) After Single Dose of HF1K16 | Cmax of tretinoin | 409 ng/mL | Standard Deviation 52.3 |
| HF1K16-3mg/m² | Peak Drug Concentration (Cmax) After Single Dose of HF1K16 | Cmax of 4-oxotretinoin | 7.65 ng/mL | Standard Deviation 0.732 |