Clinical trial NCT05388487: Tolerability and Safety of HF1K16 Injection in Patients With Refractory Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Solid Tumor, Adult
Lead sponsor: HighField Biopharmaceuticals Corporation
Sponsor class: INDUSTRY
Collaborators: name: Tigermed Consulting Co., Ltd
First posted: 2022-05-24
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of Adverse Events
timeFrame: 30 days after administration
measure: Incidence of dose-limiting toxicities(DLT)
timeFrame: 21 days after administration
measure: Respiration rate of Vital Signs by stethoscope
timeFrame: 30 days after administration
measure: Red blood cell count in whole blood sample
timeFrame: 30 days after administration
measure: Ventricular rate of ECG
timeFrame: 30 days after administration
measure: Respiration rate in mg μl/h·g of ECG
timeFrame: 30 days after administration
measure: Heart rate in beats per minute in beats per minute of ECG
timeFrame: 30 days after administration
measure: Blood pressure by sphygmomanometer
timeFrame: 30 days after administration
measure: Body temperature by thermometer
timeFrame: 30 days after administration
measure: White blood cell count in whole blood sample
timeFrame: 30 days after administration
measure: Neutrophil count in whole blood sample
timeFrame: 30 days after administration
measure: Hemoglobin concentration in g/dL in whole blood sample
timeFrame: 30 days after administration
measure: Prothrombin time in whole blood sample
timeFrame: 30 days after administration
measure: International standardized ratio in whole blood sample
timeFrame: 30 days after administration
measure: International sensitivity index in whole blood sample
timeFrame: 30 days after administration
measure: Activated partial thromboplastin time in whole blood sample
timeFrame: 30 days after administration
measure: Total bilirubin concentration in whole blood sample
timeFrame: 30 days after administration
measure: ALT concentration in whole blood sample
timeFrame: 30 days after administration
measure: AST concentration in whole blood sample
timeFrame: 30 days after administration
measure: Total protein concentration in whole blood sample
timeFrame: 30 days after administration
measure: Urea concentration in whole blood sample
timeFrame: 30 days after administration
measure: Creatinine concentration in whole blood sample
timeFrame: 30 days after administration
measure: Total cholesterol concentration in whole blood sample
timeFrame: 30 days after administration
measure: Triglycerides concentration in whole blood sample
timeFrame: 30 days after administration
measure: HDL-C in whole blood sample
timeFrame: 30 days after administration
measure: LDL-C in whole blood sample
timeFrame: 30 days after administration
measure: PR interval by ECG
timeFrame: 30 days after administration
measure: QRS by ECG
timeFrame: 30 days after administration
measure: QT by ECG
timeFrame: 30 days after administration
measure: QTc by ECG
timeFrame: 30 days after administration
measure: Cohort 5: Determination of overall response rate (ORR) according to RANO criteria
timeFrame: 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
measure: Cohort 5: Duration of response (DOR)
timeFrame: 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
measure: Cohort 5: disease control rate (DCR)
timeFrame: 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
measure: Cohort 5: progression-free survival (PFS).
timeFrame: 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 outcomes:
measure: HF1K16 pharmacokinetic parameters with Cmax
timeFrame: Up to 48 hours postdose
measure: the overall response rate(ORR) of HF1K16
timeFrame: Once every six weeks in the first year, then once every 12 weeks afterwards through study completion, an average of 1 year
measure: Peripheral blood mononuclear cells by whole blood sample
timeFrame: Before injection on Day1,7,13, 21 in each cycle（each cycle is 21 days）
measure: AUC48h by plasma concentration of whole blood sample
timeFrame: Up to 48 hours postdose
measure: Tmax by plasma concentration of whole blood sample
timeFrame: Up to 48hours postdose
measure: T1/2 by plasma concentration of whole blood sample
timeFrame: Up to 48hours postdose
measure: CL by plasma concentration of whole blood sample
timeFrame: Up to 48 hours postdose
measure: Vd by plasma concentration of whole blood sample
timeFrame: Up to 48 hours postdose
measure: AUClast by plasma concentration of whole blood sample
timeFrame: Up to 48 hours postdose
measure: Cohort 5: To assess the changes in MDSC after HF1K16 treatment, including changes in MDSC number
timeFrame: Before injection on Day1 in each cycle（each cycle is 21 days）
measure: Cohort 5: Incidence of Adverse Events
timeFrame: after administration
measure: Cohort 5: To assess the changes in MDSC after HF1K16 treatment, including changes in MDSC phenotype
timeFrame: Before injection on Day1 in each cycle（each cycle is 21 days）
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Wuhan
country: China
facility: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Shanghai
country: China
facility: Huashan Hospital Affiliated to Fudan University
state: Shanghai
city: Hangzhou
country: China
facility: First Affiliated Hospital of Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Xiaoshan Hospital
state: Zhejiang
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
Study officials:
affiliation: Huashan Hospital Shanghai
name: Jinsong Wu, MD
role: PRINCIPAL_INVESTIGATOR
References: