Tolerability and Safety of HF1K16 Injection in Patients With Refractory Solid Tumors

Overview

HF1K16 is an investigational pegylated liposome formulation of All-Trans Retinoic Acid (ATRA) 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).

Full Title of Study: “A Phase 1 Open-Label Dose-Escalation Study to Evaluate the Tolerability, DLT, Pharmacokinetics, and Preliminary Efficacy of HF1K16 in Patients With Refractory Solid Tumors”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2022

Detailed Description

Myeloid Derived Suppressor Cells (MDSCs) play important roles in constituting the immune suppressive environment promoting cancer development and progression. While previous studies had shown that all-trans retinoic acid (ATRA) could induce MDSC differentiation and maturation, the very poor solubility and fast metabolism of the drug limited its applications as an immune-modulator for cancer immunotherapy HF1K16 is an investigational pegylated liposome formulation with great ATRA dose loading capacity and sustained drug release property. In preclinical studies, HF1K16 was shown to be able to remodel the host systemic immune homeostasis as well as modify tumor microenvironment (TME). It promotes MDSCs maturation into DCs and facilitates immune responses against cancer cells.

Interventions

  • Drug: HF1K16 /Arm 45 mg/m2
    • HF1K16 is a liposome suspension containing encapsulated ATRA. Drug concentration is 2mg/ml, and infusion should be completed between 60 minutes and 90 minutes
  • Drug: HF1K16 /Arm 90 mg/m2
    • HF1K16 is a liposome suspension containing encapsulated ATRA. Drug concentration is 2mg/ml, and infusion should be completed between 60 minutes and 90 minutes
  • Drug: HF1K16 /Arm 120 mg/m2
    • HF1K16 is a liposome suspension containing encapsulated ATRA. Drug concentration is 2mg/ml, and infusion should be completed between 60 minutes and 90 minutes
  • Drug: HF1K16 /Arm 160 mg/m2
    • HF1K16 is a liposome suspension containing encapsulated ATRA. Drug concentration is 2mg/ml, and infusion should be completed between 60 minutes and 90 minutes

Arms, Groups and Cohorts

  • Experimental: Dose escalation cohort 1: HF1K16 given QOD at 45 mg/m2
    • The first dosing group (45 mg/m2) will include a sentinel subject receiving one dose followed by a 7-day safety evaluation interval. Three or more subjects will receive 7 doses of HF1K16 QOD at 45 mg/m2 per cycle of 21 days.
  • Experimental: Dose escalation cohort 2: Oral ATRA followed by HF1K16 QOD at 90 mg/m2
    • The second dosing group will receive oral ATRA at 45mg/m2, and three days later HF1K16 QOD at 90 mg/m2 for 7 times per cycle of 21 days.
  • Experimental: Dose escalation cohort 3: HF1K16 QOD at 120 mg/m2
    • The cohort 3 will receive 7 doses of HF1K16 QOD at 120 mg/m per cycle of 21 days.
  • Experimental: Dose escalation cohort 4: HF1K16 QOD at 160 mg/m2
    • The cohort 3 will receive 7 doses of HF1K16 QOD at 160 mg/m per cycle of 21 days.

Clinical Trial Outcome Measures

Primary Measures

  • Incidence of Adverse Events
    • Time Frame: 30 days after administration
    • Defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0)
  • Incidence of dose-limiting toxicities(DLT)
    • Time Frame: 21 days after administration
    • Observe the dose limiting toxicity, and Incidence of dose-limiting toxicities(DLT) will be assessed
  • Respiration rate of Vital Signs by stethoscope
    • Time Frame: 30 days after administration
    • Changes from baseline for respiration rate in breaths per minute of Vital Signs
  • Red blood cell count in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for Red blood cell count in whole blood in10^9 /L
  • Ventricular rate of ECG
    • Time Frame: 30 days after administration
    • Changes from baseline for ventricular rate in beats per minute
  • Respiration rate in mg μl/h·g of ECG
    • Time Frame: 30 days after administration
    • Changes from baseline for respiration rate in mg μl/h·g
  • Heart rate in beats per minute in beats per minute of ECG
    • Time Frame: 30 days after administration
    • Changes from baseline for heart rate in beats per minute
  • Blood pressure by sphygmomanometer
    • Time Frame: 30 days after administration
    • Changes from baseline for blood pressure in mmHg, both systolic and diastolic pressures will be assessed.
  • Body temperature by thermometer
    • Time Frame: 30 days after administration
    • Changes from baseline for body temperature in Celsius degree
  • White blood cell count in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for white blood cell count in whole blood in 10^9 /L
  • Neutrophil count in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for neutrophil count in whole blood in 10^9 /L
  • Hemoglobin concentration in g/dL in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for hemoglobin concentration in g/dL in whole blood
  • Prothrombin time in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for Prothrombin time in s
  • International standardized ratio in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for international standardized ratio
  • International sensitivity index in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for international sensitivity index
  • Activated partial thromboplastin time in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for activated partial thromboplastin time in s
  • Total bilirubin concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for total bilirubin concentration in μmol/L
  • ALT concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for alanine aminotransferase(ALT) concentration in U/L
  • AST concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for aspartate aminotransferase(AST) concentration in U/L
  • Total protein concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for total protein concentration in g/L
  • Urea concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for urea concentration in mmol/L
  • Creatinine concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for creatinine concentration in μmol/L
  • Total cholesterol concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for total cholesterol concentration in mmol/L
  • Triglycerides concentration in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for triglycerides concentration in mmol/L
  • HDL-C in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for high density lipoprotein cholesterol (HDL-C) in mmol/L
  • LDL-C in whole blood sample
    • Time Frame: 30 days after administration
    • Changes from baseline for low density lipoprotein cholesterol (LDL-C) in mmol/L
  • PR interval by ECG
    • Time Frame: 30 days after administration
    • Changes from baseline for PR interval in ms of ECG
  • QRS by ECG
    • Time Frame: 30 days after administration
    • Changes from baseline for QRS in ms of ECG
  • QT by ECG
    • Time Frame: 30 days after administration
    • Changes from baseline for QT in ms of ECG
  • QTc by ECG
    • Time Frame: 30 days after administration
    • Changes from baseline for QTc in ms of ECG

Secondary Measures

  • HF1K16 pharmacokinetic parameters with Cmax
    • Time Frame: Up to 48 hours postdose
    • Maximum plasma concentration (Cmax) after administration of HF1K16
  • the overall response rate(ORR) of HF1K16
    • Time Frame: Once every six weeks in the first year, then once every 12 weeks afterwards through study completion, an average of 1 year
    • ORR is defined as the proportion of participants with complete response or partial response (CR+PR)
  • Peripheral blood mononuclear cells by whole blood sample
    • Time Frame: Before injection on Day1,7,13, 21 in each cycle(each cycle is 21 days)
    • Assessing peripheral blood mononuclear cells after dose in cells/mL
  • AUC48h by plasma concentration of whole blood sample
    • Time Frame: Up to 48 hours postdose
    • Area under plasma concentration -time curve from 0 time ot 48 h(AUC0-48) after dose
  • Tmax by plasma concentration of whole blood sample
    • Time Frame: Up to 48hours postdose
    • Peak time (Tmax) after dose
  • T1/2 by plasma concentration of whole blood sample
    • Time Frame: Up to 48hours postdose
    • Elimination half-life (T1/2) after dose
  • CL by plasma concentration of whole blood sample
    • Time Frame: Up to 48 hours postdose
    • Clearance (CL) after dose
  • Vd by plasma concentration of whole blood sample
    • Time Frame: Up to 48 hours postdose
    • Volume of distribution(Vd) after dose
  • AUClast by plasma concentration of whole blood sample
    • Time Frame: Up to 48 hours postdose
    • Ratios of geometric means of AUClast (Area under the plasma concentration-time curve from zero to time of last quantifiable concentration) after dose

Participating in This Clinical Trial

Inclusion Criteria

1, Willing and able to provide the test of informed consent in writing. 2. Male or female, age > 18 years and < = 75 years. 3. The subjects had to be diagnosed by histology and/or cytology with locally advanced or metastatic solid tumor. There is no effective standard of care or the patient is intolerant to the standard therapy. 4. According to the definition of RECIST 1.1, participants must have at least one measurable lesion. 5, Eastern group (ECOG) tumor physical state to 0 or 1. 6, Expected lifetime > 12 weeks. 7, Men or women of childbearing age must agree to adopt effective contraception after signing the informed consent form until 180 days after the end of the study. Premenopausal women or those within 2 years after menopause are included. Exclusion Criteria:

1, Patients received systemic antitumor therapy, including chemotherapy, radiotherapy, biologic therapy, endocrine therapy, or immunotherapy within 3 weeks prior to the first dose, except for the following: Nitrosoureas or mitomycin C within 6 weeks; Oral fluorouracils and small molecule drugs within 2 weeks or within 5 half-life periods of the drug (whichever is longer); Antitumour traditional Chinese medicine within 2 weeks. 2.Adverse effects of previous anti-tumor therapy have not recovered to CTCAE 5.0 grade rating of ≤ grade 1 (except for toxicity judged by the investigator be of no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, etc.) 3.Patients received other unlisted clinical trial drugs or treatments within 28 days prior to the first dose. 4.Taken vitamin A or any vitamin A derivatives within 7 days prior to the first dose. 5, Past history of deep vein thrombosis or pulmonary embolism. 6, Evidence that there is poor control of thyroid diseases, or diseases of the retina. 7. Patients have symptomatic central nervous system (CNS) metastases, meningeal metastases, or a primary CNS tumor that is associated with progressive neurological symptoms. Except that the brain metastases are shown to be stable judged by imaging examination within 4 weeks. 8. Evidences of serious or uncontrolled systemic disease (for example: instability or decompensated respiratory disease, liver or kidney disease) 9. Serious liver and kidney function damage; 10. Has clinical significance of cardiovascular disease; 11. Have known immune inhibitory disease or human immunodeficiency virus (HIV) infection. 12. Patients with severe osteoporosis or bone metastasis, and serum 25 – light で vitamin D values is less than 50 nmol/L 13. Active hepatitis (Hepatitis B: HBsAg-positive and HBV-DNA ≥ 500 cps/mL or 200 IU/mLL; HCV RNA-positive). 14. Persons with known hypersensitivity to any of the active ingredients or excipients or a history of atopic allergic reactions. 15. The pregnancy test positive (blood beta human chorionic gonadotropin – HCG [B] test positive) or lactationWomen. 16. Researchers believe that patients with combined disease may affect the compliance. 17, Participants not willing to or fail to follow the procedure.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • HighField Biopharmaceuticals Corporation
  • Collaborator
    • Tigermed Consulting Co., Ltd
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Jinsong Wu, Principal Investigator, Huashan Hospital Shanghai
  • Overall Contact(s)
    • Yongfeng Huang, +86-13916925827, huangyf@hf-biopharm.com

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