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

Solid Tumor, Adult Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05388487
• Other study ID #: HF1K16-101(CN)
• Status: Recruiting
• Phase: Phase 1
• Start date: February 16, 2022
• Est. completion date: November 2025

Study information

• Verified date: January 2024
• Source: HighField Biopharmaceuticals Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 54
• Est. completion date: November 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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. Cohort 5: The subjects must be diagnosed with glioma by histology, and the disease has relapsed or progressed after previous treatment, and there is no effective standard treatment or the subject is intolerant to standard treatment.

4. According to the definition of RECIST 1.1, participants must have at least one measurable lesion. Cohort 5: at least one lesion that can be measured in two dimensions is required ( RANO criteria).

5. Eastern group (ECOG) tumor physical state to 0 or 1. Cohort 5: According to Karnofsky physical fitness score = 60.

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. Cohort 5: The above criteria do not apply to the fifth cohort. The fifth cohort allowed inhaled or topical corticosteroids, or hormone therapy at physiological replacement doses due to adrenal insufficiency; short-term (=7 days) corticosteroids were allowed for prophylaxis (eg, contrast media allergy) or treatment of non-autoimmune conditions ( For example, delayed-type hypersensitivity reactions caused by exposure to allergens); systemic corticosteroids (=10 mg/day prednisone, or other equivalent corticosteroids) for 7 consecutive days within 14 days of the first dose are not allowed or Immunosuppressant therapy.

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 with bone metastases with serum 25-hydroxyvitamin D assay values 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.

18. Cohort 5: Brain MRI not available.

19. Cohort 5: uncontrolled epilepsy.

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumor, Adult

Intervention

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
• 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
• 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
• 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
• HF1K16 /Arm 120 mg or 180 mg
HF1K16 is a liposome suspension containing encapsulated ATRA. Drug concentration is 2mg/ml, and infusion should be completed between 60 minutes and 90 minutes

Locations

Country	Name	City	State
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong
China	First Affiliated Hospital of Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	Zhejiang Xiaoshan Hospital	Hangzhou	Zhejiang
China	Huashan Hospital Affiliated to Fudan University	Shanghai	Shanghai
China	The First Affiliated Hospital of Wenzhou Medical University	Wenzhou	Zhejiang
China	Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan

Sponsors (2)

Lead Sponsor	Collaborator
HighField Biopharmaceuticals Corporation	Tigermed Consulting Co., Ltd

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Adverse Events	Defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0)	30 days after administration
Primary	Incidence of dose-limiting toxicities(DLT)	Observe the dose limiting toxicity, and Incidence of dose-limiting toxicities(DLT) will be assessed	21 days after administration
Primary	Respiration rate of Vital Signs by stethoscope	Changes from baseline for respiration rate in breaths per minute of Vital Signs	30 days after administration
Primary	Red blood cell count in whole blood sample	Changes from baseline for Red blood cell count in whole blood in10^9 /L	30 days after administration
Primary	Ventricular rate of ECG	Changes from baseline for ventricular rate in beats per minute	30 days after administration
Primary	Respiration rate in mg µl/h·g of ECG	Changes from baseline for respiration rate in mg µl/h·g	30 days after administration
Primary	Heart rate in beats per minute in beats per minute of ECG	Changes from baseline for heart rate in beats per minute	30 days after administration
Primary	Blood pressure by sphygmomanometer	Changes from baseline for blood pressure in mmHg, both systolic and diastolic pressures will be assessed.	30 days after administration
Primary	Body temperature by thermometer	Changes from baseline for body temperature in Celsius degree	30 days after administration
Primary	White blood cell count in whole blood sample	Changes from baseline for white blood cell count in whole blood in 10^9 /L	30 days after administration
Primary	Neutrophil count in whole blood sample	Changes from baseline for neutrophil count in whole blood in 10^9 /L	30 days after administration
Primary	Hemoglobin concentration in g/dL in whole blood sample	Changes from baseline for hemoglobin concentration in g/dL in whole blood	30 days after administration
Primary	Prothrombin time in whole blood sample	Changes from baseline for Prothrombin time in s	30 days after administration
Primary	International standardized ratio in whole blood sample	Changes from baseline for international standardized ratio	30 days after administration
Primary	International sensitivity index in whole blood sample	Changes from baseline for international sensitivity index	30 days after administration
Primary	Activated partial thromboplastin time in whole blood sample	Changes from baseline for activated partial thromboplastin time in s	30 days after administration
Primary	Total bilirubin concentration in whole blood sample	Changes from baseline for total bilirubin concentration in µmol/L	30 days after administration
Primary	ALT concentration in whole blood sample	Changes from baseline for alanine aminotransferase(ALT) concentration in U/L	30 days after administration
Primary	AST concentration in whole blood sample	Changes from baseline for aspartate aminotransferase(AST) concentration in U/L	30 days after administration
Primary	Total protein concentration in whole blood sample	Changes from baseline for total protein concentration in g/L	30 days after administration
Primary	Urea concentration in whole blood sample	Changes from baseline for urea concentration in mmol/L	30 days after administration
Primary	Creatinine concentration in whole blood sample	Changes from baseline for creatinine concentration in µmol/L	30 days after administration
Primary	Total cholesterol concentration in whole blood sample	Changes from baseline for total cholesterol concentration in mmol/L	30 days after administration
Primary	Triglycerides concentration in whole blood sample	Changes from baseline for triglycerides concentration in mmol/L	30 days after administration
Primary	HDL-C in whole blood sample	Changes from baseline for high density lipoprotein cholesterol (HDL-C) in mmol/L	30 days after administration
Primary	LDL-C in whole blood sample	Changes from baseline for low density lipoprotein cholesterol (LDL-C) in mmol/L	30 days after administration
Primary	PR interval by ECG	Changes from baseline for PR interval in ms of ECG	30 days after administration
Primary	QRS by ECG	Changes from baseline for QRS in ms of ECG	30 days after administration
Primary	QT by ECG	Changes from baseline for QT in ms of ECG	30 days after administration
Primary	QTc by ECG	Changes from baseline for QTc in ms of ECG	30 days after administration
Primary	Cohort 5: Determination of overall response rate (ORR) according to RANO criteria	ORR is defined as the proportion of participants with complete response or partial response (CR+PR)	From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 weeks
Primary	Cohort 5: Duration of response (DOR)	DOR, defined as the time between the start of the subject's first assessment of CR or PR and the first assessment of PD or death from any cause, according to RANO criteria by the investigator	From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 weeks
Primary	Cohort 5: disease control rate (DCR)	DCR , defined as the proportion of subjects with a best overall response of CR, PR, or SD in the study as assessed by the investigator according to RANO criteria	From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 weeks
Primary	Cohort 5: progression-free survival (PFS).	PFS, defined as the time between the subject's first dose and the onset of (any aspect of) tumor progression or death from any cause	From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 weeks
Secondary	HF1K16 pharmacokinetic parameters with Cmax	Maximum plasma concentration (Cmax) after administration of HF1K16	Up to 48 hours postdose
Secondary	the overall response rate(ORR) of HF1K16	ORR is defined as the proportion of participants with complete response or partial response (CR+PR)	Once every six weeks in the first year, then once every 12 weeks afterwards through study completion, an average of 1 year
Secondary	Peripheral blood mononuclear cells by whole blood sample	Assessing peripheral blood mononuclear cells after dose in cells/mL	Before injection on Day1,7,13, 21 in each cycle(each cycle is 21 days)
Secondary	AUC48h by plasma concentration of whole blood sample	Area under plasma concentration -time curve from 0 time ot 48 h(AUC0-48) after dose	Up to 48 hours postdose
Secondary	Tmax by plasma concentration of whole blood sample	Peak time (Tmax) after dose	Up to 48hours postdose
Secondary	T1/2 by plasma concentration of whole blood sample	Elimination half-life (T1/2) after dose	Up to 48hours postdose
Secondary	CL by plasma concentration of whole blood sample	Clearance (CL) after dose	Up to 48 hours postdose
Secondary	Vd by plasma concentration of whole blood sample	Volume of distribution(Vd) after dose	Up to 48 hours postdose
Secondary	AUClast by plasma concentration of whole blood sample	Ratios of geometric means of AUClast (Area under the plasma concentration-time curve from zero to time of last quantifiable concentration) after dose	Up to 48 hours postdose
Secondary	Cohort 5: To assess the changes in MDSC after HF1K16 treatment, including changes in MDSC number	Assessing peripheral blood mononuclear cells after dose in cells/mL	Before injection on Day1 in each cycle(each cycle is 21 days)
Secondary	Cohort 5: Incidence of Adverse Events	Defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0)	after administration
Secondary	Cohort 5: To assess the changes in MDSC after HF1K16 treatment, including changes in MDSC phenotype	Assessment of MDSC phenotype in peripheral blood after drug administration	Before injection on Day1 in each cycle(each cycle is 21 days)