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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 54
- 试验地点
- 7
- 主要终点
- Incidence of dose-limiting toxicities(DLT)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to provide the test of informed consent in writing.
- •Male or female, age > 18 years and < = 75 years.
- •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.
- •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).
- •Eastern group (ECOG) tumor physical state to 0 or
- •Cohort 5: According to Karnofsky physical fitness score ≥
- •Expected lifetime > 12 weeks.
- •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.
排除标准
- •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.
- •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.)
- •Patients received other unlisted clinical trial drugs or treatments within 28 days prior to the first dose.
- •Taken vitamin A or any vitamin A derivatives within 7 days prior to the first dose.
- •Past history of deep vein thrombosis or pulmonary embolism.
- •Evidence that there is poor control of thyroid diseases, or diseases of the retina.
- •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.
- •Evidences of serious or uncontrolled systemic disease (for example: instability or decompensated respiratory disease, liver or kidney disease)
- •Serious liver and kidney function damage;
- •Has clinical significance of cardiovascular disease;
- •Have known immune inhibitory disease or human immunodeficiency virus (HIV) infection.
- •Patients with severe osteoporosis or with bone metastases with serum 25-hydroxyvitamin D assay values less than 50 nmol/L.
- •Active hepatitis (Hepatitis B: HBsAg-positive and HBV-DNA ≥ 500 cps/mL or 200 IU/mLL; HCV RNA-positive).
- •Persons with known hypersensitivity to any of the active ingredients or excipients or a history of atopic allergic reactions.
- •The pregnancy test positive (blood beta human chorionic gonadotropin - HCG [B] test positive) or lactationWomen.
- •Researchers believe that patients with combined disease may affect the compliance.
- •Participants not willing to or fail to follow the procedure.
- •Cohort 5: Brain MRI not available.
- •Cohort 5: uncontrolled epilepsy.
研究组 & 干预措施
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.
干预措施: HF1K16 /Arm 45 mg/m² (Drug)
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.
干预措施: HF1K16 /Arm 90 mg/m² (Drug)
Dose escalation cohort 3: HF1K16 QOD at 120 mg/m²
The cohort 3 will receive 7 doses of HF1K16 QOD at 120 mg/m² per cycle of 21 days.
干预措施: HF1K16 /Arm 120 mg/m² (Drug)
Dose escalation cohort 4: HF1K16 QOD at 160 mg/m²
The cohort 4 will receive 7 doses of HF1K16 QOD at 160 mg/m² per cycle of 21 days.
干预措施: HF1K16 /Arm 160 mg/m² (Drug)
Dose escalation cohort 5: HF1K16 QOD at 120mg or180 mg
The cohort 5 will receive 7 doses of HF1K16 QOD at 120 mg or 180mg per cycle of 21 days.
干预措施: HF1K16 /Arm 120 mg or 180 mg (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicities(DLT)
时间窗: 21 days after administration
Observe the dose limiting toxicity, and Incidence of dose-limiting toxicities(DLT) will be assessed
Heart rate in beats per minute in beats per minute of ECG
时间窗: 30 days after administration
Changes from baseline for heart rate in beats per minute
Total bilirubin concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for total bilirubin concentration in μmol/L
Incidence of Adverse Events
时间窗: 30 days after administration
Defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0)
Respiration rate of Vital Signs by stethoscope
时间窗: 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
时间窗: 30 days after administration
Changes from baseline for Red blood cell count in whole blood in10\^9 /L
Ventricular rate of ECG
时间窗: 30 days after administration
Changes from baseline for ventricular rate in beats per minute
Respiration rate in mg μl/h·g of ECG
时间窗: 30 days after administration
Changes from baseline for respiration rate in mg μl/h·g
Blood pressure by sphygmomanometer
时间窗: 30 days after administration
Changes from baseline for blood pressure in mmHg, both systolic and diastolic pressures will be assessed.
Body temperature by thermometer
时间窗: 30 days after administration
Changes from baseline for body temperature in Celsius degree
White blood cell count in whole blood sample
时间窗: 30 days after administration
Changes from baseline for white blood cell count in whole blood in 10\^9 /L
Hemoglobin concentration in g/dL in whole blood sample
时间窗: 30 days after administration
Changes from baseline for hemoglobin concentration in g/dL in whole blood
International standardized ratio in whole blood sample
时间窗: 30 days after administration
Changes from baseline for international standardized ratio
ALT concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for alanine aminotransferase(ALT) concentration in U/L
Neutrophil count in whole blood sample
时间窗: 30 days after administration
Changes from baseline for neutrophil count in whole blood in 10\^9 /L
Prothrombin time in whole blood sample
时间窗: 30 days after administration
Changes from baseline for Prothrombin time in s
International sensitivity index in whole blood sample
时间窗: 30 days after administration
Changes from baseline for international sensitivity index
Activated partial thromboplastin time in whole blood sample
时间窗: 30 days after administration
Changes from baseline for activated partial thromboplastin time in s
AST concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for aspartate aminotransferase(AST) concentration in U/L
Urea concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for urea concentration in mmol/L
Creatinine concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for creatinine concentration in μmol/L
Total cholesterol concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for total cholesterol concentration in mmol/L
HDL-C in whole blood sample
时间窗: 30 days after administration
Changes from baseline for high density lipoprotein cholesterol (HDL-C) in mmol/L
PR interval by ECG
时间窗: 30 days after administration
Changes from baseline for PR interval in ms of ECG
QT by ECG
时间窗: 30 days after administration
Changes from baseline for QT in ms of ECG
Total protein concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for total protein concentration in g/L
LDL-C in whole blood sample
时间窗: 30 days after administration
Changes from baseline for low density lipoprotein cholesterol (LDL-C) in mmol/L
Triglycerides concentration in whole blood sample
时间窗: 30 days after administration
Changes from baseline for triglycerides concentration in mmol/L
QRS by ECG
时间窗: 30 days after administration
Changes from baseline for QRS in ms of ECG
QTc by ECG
时间窗: 30 days after administration
Changes from baseline for QTc in ms of ECG
Cohort 5: Determination of overall response rate (ORR) according to RANO criteria
时间窗: 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
ORR is defined as the proportion of participants with complete response or partial response (CR+PR)
Cohort 5: Duration of response (DOR)
时间窗: 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
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
Cohort 5: progression-free survival (PFS).
时间窗: 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
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
Cohort 5: disease control rate (DCR)
时间窗: 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
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
次要结局
- HF1K16 pharmacokinetic parameters with Cmax(Up to 48 hours postdose)
- Tmax by plasma concentration of whole blood sample(Up to 48hours postdose)
- Cohort 5: To assess the changes in MDSC after HF1K16 treatment, including changes in MDSC number(Before injection on Day1 in each cycle（each cycle is 21 days）)
- Cohort 5: Incidence of Adverse Events(after administration)
- the overall response rate(ORR) of HF1K16(Once every six weeks in the first year, then once every 12 weeks afterwards through study completion, an average of 1 year)
- AUC48h by plasma concentration of whole blood sample(Up to 48 hours postdose)
- Peripheral blood mononuclear cells by whole blood sample(Before injection on Day1,7,13, 21 in each cycle（each cycle is 21 days）)
- T1/2 by plasma concentration of whole blood sample(Up to 48hours postdose)
- CL by plasma concentration of whole blood sample(Up to 48 hours postdose)
- Vd by plasma concentration of whole blood sample(Up to 48 hours postdose)
- AUClast by plasma concentration of whole blood sample(Up to 48 hours postdose)
- Cohort 5: To assess the changes in MDSC after HF1K16 treatment, including changes in MDSC phenotype(Before injection on Day1 in each cycle（each cycle is 21 days）)