HF158K1 is an investigational liposome form of doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, encapsulated by lipid membranes containing TL01, a HER2-directed Trastuzumab Fab fragment conjugated lipid.
This study is a multi-regional, open-label, multiple-dose administration dose-escalation and dose-expansion study, including a Dose-Escalation Phase (Ia) and a Dose-Expansion Phase (Ib). HF158K1 contains multiple copies of the targeting antibody on liposome surface. It is designed to bind and deliver the chemotherapeutic doxorubicin to tumor cells at even very low HER2 expression levels. The study recruits patients with unresectable or metastatic advanced solid tumors (HER-2 positive (IHC 3+, or IHC 2+ with ISH +) or HER-2 low expression (IHC 2+ with ISH -, or IHC 1+)) who have failed or are intolerant (disease progression, or intolerance to chemotherapy, targeted therapy, etc.) to standard treatment, or currently have no available treatment regimen. Phase 1a(Dose escalation) will assess the safety，tolerability，pharmacokinetics of HF158K1 in participants to determine the maximum tolerated dose (MTD) of HF158K1 through the incidence of dose-limiting toxicity (DLT). Phase 1b(Dose expansion) will assess safety and preliminary efficacy of HF158K1 in participants with specific tumor types in selected dose groups.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
84
Duration of infusion: HF158K1 is diluted using 5% (50 mg/ml) glucose injection or 0.9% sodium chloride injection (saline) to a total volume of 250 ml and is administered through intravenous infusion for 90 ± 10 min.
Duration of infusion: HF158K1 is diluted using 5% (50 mg/ml) glucose injection or 0.9% sodium chloride injection (saline) to a total volume of 250 ml and is administered through intravenous infusion for 90 ± 10 min.
Duration of infusion: HF158K1 is diluted using 5% (50 mg/ml) glucose injection or 0.9% sodium chloride injection (saline) to a total volume of 250 ml and is administered through intravenous infusion for 90 ± 10 min.
Mary Crowley Cancer Research
Dallas, Texas, United States
RECRUITINGIncidence of Adverse Events
Defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0)
Time frame: The period of AE collection starts after the participant receives the investigational drug, until 28±3 days after the EOT/early withdrawal or before the participant starts another anti-tumor treatment (whichever occurs first).
Incidence of dose-limiting toxicities(DLT)
Observe the dose limiting toxicity, and Incidence of dose-limiting toxicities(DLT) will be assessed
Time frame: The DLT evaluation period is from the first administration of the investigational drug to the end of the first treatment cycle, lasting for 21 days.（only Ia）
Red blood cell count in whole blood sample
Changes from baseline for Red blood cell count in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
White blood cell in whole blood sample
Changes from baseline for white blood cell count in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Hematocrit in whole blood sample
Changes from baseline for Hematocrit in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Neutrophil count in whole blood sample
Changes from baseline for neutrophil count in whole blood
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Duration of infusion: HF158K1 is diluted using 5% (50 mg/ml) glucose injection or 0.9% sodium chloride injection (saline) to a total volume of 250 ml and is administered through intravenous infusion for 90 ± 10 min.
Duration of infusion: HF158K1 is diluted using 5% (50 mg/ml) glucose injection or 0.9% sodium chloride injection (saline) to a total volume of 250 ml and is administered through intravenous infusion for 90 ± 10 min.
Duration of infusion: HF158K1 is diluted using 5% (50 mg/ml) glucose injection or 0.9% sodium chloride injection (saline) to a total volume of 250 ml and is administered through intravenous infusion for 90 ± 10 min.
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Hemoglobin concentration in whole blood sample
Changes from baseline for hemoglobin concentration in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Percentage of lymphocytes (LYM%)
Changes from baseline for Percentage of lymphocytes (LYM%) in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Lymphocyte count
Changes from baseline for Lymphocyte count in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Percentage of neutrophils (NEU%) Percentage of neutrophils (NEU%)
Changes from baseline for Percentage of neutrophils (NEU%) in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Platelet count in whole blood sample
Changes from baseline for Platelet count in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Prothrombin time in whole blood sample
Changes from baseline for Prothrombin time in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
International normalized ratio in whole blood sample
Changes from baseline for international standardized ratio in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Fibrinogen in whole blood sample
Changes from baseline for Fibrinogen in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Activated partial prothrombin time in whole blood sample
Changes from baseline for activated partial thromboplastin time in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Total bilirubin concentration in whole blood sample
Changes from baseline for total bilirubin concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
ALT concentration in whole blood sample
Changes from baseline for alanine aminotransferase(ALT) concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
AST concentration in whole blood sample
Changes from baseline for aspartate aminotransferase(AST) concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Total protein concentration in whole blood sample
Changes from baseline for total protein concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Urea concentration in whole blood sample
Changes from baseline for urea concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Creatinine concentration in whole blood sample
Changes from baseline for creatinine concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Total cholesterol concentration in whole blood sample
Changes from baseline for total cholesterol concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Triglycerides concentration in whole blood sample
Changes from baseline for triglycerides concentration in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
HDL-C in whole blood sample
Changes from baseline for high density lipoprotein cholesterol (HDL-C) in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
LDL-C in whole blood sample
Changes from baseline for low density lipoprotein cholesterol (LDL-C) in whole blood sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Glucose in whole blood sample
Changes from baseline for Lactic dehydrogenase in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Alkaline phosphatase in whole blood sample
Changes from baseline for Lactic dehydrogenase in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Lactic dehydrogenase in whole blood sample
Changes from baseline for Lactic dehydrogenase in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Gamma-glutamyl transferase in whole blood sample
Changes from baseline for Gamma-glutamyl transferase in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Albumin in whole blood sample
Changes from baseline for Albumin in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Direct bilirubin in whole blood sample
Changes from baseline for Direct bilirubin in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Sodium in whole blood sample
Changes from baseline for Sodium in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Potassium in whole blood sample
Changes from baseline for Potassium in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Chloride in whole blood sample
Changes from baseline for Chloride in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Calcium in whole blood sample
Changes from baseline for Calcium in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Phosphate in whole blood sample
Changes from baseline for Phosphate in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Uric acid in whole blood sample
Changes from baseline for Uric acid in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Creatine kinase in whole blood sample
Changes from baseline for Creatine kinase in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Creatine kinase isoenzyme in whole blood sample
Changes from baseline for Creatine kinase isoenzyme in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Troponin-T (TnT) in whole blood sample
Changes from baseline for Troponin-T in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Troponin-I (TnI) in whole blood sample
Changes from baseline for Troponin-I in whole blood
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Urine protein in urine sample
Changes from baseline for Urine protein in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Red blood cells in urine sample
Changes from baseline for Red blood cells in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
White blood cells in urine sample
Changes from baseline for White blood cells in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
PH in urine sample
Changes from baseline for pH in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Ketone bodies in urine sample
Changes from baseline for Ketone bodies in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Urine glucose in urine sample
Changes from baseline for Urine glucose in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Urine bilirubin in urine sample
Changes from baseline for Urine bilirubin in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Urine occult blood in urine sample
Changes from baseline for Urine occult blood in urine sample
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Heart Rate in beats per minute in beats per minute of ECG
Changes from baseline for heart rate in beats per minute
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
RR Interval by ECG
Changes from baseline for RR interval by ECG
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
PR Interval by ECG
Changes from baseline for PR interval by ECG
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
QRS Interval by ECG
Changes from baseline for QRS interval by ECG
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
QT Interval by ECG
Changes from baseline for QT interval by ECG
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
QTcF by ECG
Changes from baseline for QTcF interval by ECG
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Left ventricular ejection fraction measured by Echocardiography
Changes from baseline for Left ventricular ejection fraction measured by Echocardiography
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Body (Ear) Temperature measurement in Vital Signs
Changes from baseline for Body (Ear) Temperature
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Pulse measurement in Vital Signs
Changes from baseline for Pulse
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Respiration Rate measurement in Vital Signs
Changes from baseline for respiration rate in breaths of Vital Signs
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Sitting Systolic Blood Pressure
Changes from baseline for Sitting Systolic Blood Pressure
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
Sitting Diastolic Blood Pressure
Changes from baseline for Sitting Diastolic Blood Pressure
Time frame: This should be evaluated during the screening period, on Day 1, 8, 15 of each cycle (each cycle is 21 days) , Day 1 of each subsequent cycle, at the EOT/early withdrawal and safety follow-up.
The recommended Phase II dose
Determine the Recommended Phase II Dose(mg/㎡) of HF158K1 and provide references for dose selection in future clinical studies.
Time frame: After the end of the dose Expansion Phase（only Ib）
Determine the maximum tolerated dose
The dose at which the incidence of DLT was closest to the target probability of toxicity (30%).
Time frame: The first administration of the investigational drug to the end of the first treatment cycle, lasting for 21 days.
HF158K1 pharmacokinetic parameters with Cmax
Maximum plasma concentration (Cmax) after administration of HF158K1
Time frame: Within 336 hours after the first and second administration
AUC by plasma concentration of whole blood sample
Area under plasma concentration -time curve after dose
Time frame: Within 336 hours after the first and second administration
Tmax by plasma concentration of whole blood sample
Peak time (Tmax) after dose
Time frame: Within 336 hours after the first and second administration
T1/2 by plasma concentration of whole blood sample
Elimination half-life (T1/2) after dose
Time frame: Within 336 hours after the first and second administration
CL by plasma concentration of whole blood sample
Clearance (CL) after dose
Time frame: Within 336 hours after the first and second administration
Vd by plasma concentration of whole blood sample
Volume of distribution(Vd) after dose
Time frame: Within 336 hours after the first and second administration
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
Time frame: Within 336 hours after the first and second administration
The objective response rate(ORR) of HF158K1
ORR is defined as the proportion of participants with complete response or partial response (CR+PR)
Time frame: ORR will be calculated for all participants who have received the investigational drug at least once and have undergone at least one tumor evaluation after administration, assessed up to 51 weeks.
disease control rate (DCR) of HF158K1
DCR is defined as the proportion of participants with complete response stable disease and partial response (CR+PR+SD)
Time frame: DCR will be calculated for all participants who have received the investigational drug at least once and have undergone at least one tumor evaluation after administration, assessed up to 51 weeks.
duration of response(DOR) of HF158K1
For duration of response (DOR), the Kaplan-Meier survival curve will be plotted to analyze their maximum, minimum, median and 95% confidence interval descriptively statistically.
Time frame: DOR will be calculated for all participants who have received the investigational drug at least once and have undergone at least one tumor evaluation after administration, assessed up to 51 weeks.
Analysis of immunogenicity
Immunogenicity analyses related to anti-TL01 antibody will be performed based on IMS(Immunogenicity Analysis Set).
Time frame: On the first day of the first cycle, on the first day of the fourth cycle, on the 21st day of the eighth cycle