Solid Tumors, Adult
Conditions
Brief summary
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.
Detailed description
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 bridging) will be conducted in Chinese patients to bridge the safety and pharmacokinetic data between different ethnic populations. Phase 1c(Dose expansion) will assess safety and preliminary efficacy of HF158K1 in participants with specific tumor types in selected dose groups.
Interventions
DRUGHF158K1 / 1.4 g lipid dose
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.
DRUGHF158K1 / 2.2 g lipid dose
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.
DRUGHF158K1 / 2.9 g lipid dose
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.
Sponsors
HighField Biopharmaceuticals Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntary to participate and sign ICF. 2. Age ≥ 18 and ≤ 75 years. 3. Unresectable or metastatic advanced solid tumors with HER-2 expression (IHC 3+, 2+, or 1+). 4. ECOG score 0-1. 5. Expected survival ≥ 6 months. 6. At least one measurable lesion per RECIST v1.1. 7. Adequate organ function: ANC ≥ 1.5×10⁹/L, LYM ≥ 1.0×10⁹/L, PLT ≥ 90×10⁹/L, HGB ≥ 8.0 g/dL; APTT ≤ 1.5×ULN, INR ≤ 1.5; TBIL ≤ 1.5×ULN, ALT/AST ≤ 2.5×ULN (≤ 5×ULN if liver metastases); CrCl ≥ 30 mL/min; LVEF ≥ 50%. 8. Agreement to use effective contraception.
Exclusion criteria
1. Cumulative doxorubicin dose ≥ 350 mg/m² or prior anthracycline-induced cardiotoxicity. 2. Current use of immunosuppressants or systemic corticosteroids (\> 10 mg/day prednisone). 3. Prior anti-tumor therapy \< 2 weeks (4 weeks for nitrosourea/mitomycin C). 4. Symptomatic CNS metastases. 5. Unresolved AEs from prior therapy \> Grade 1. 6. Serious cardiovascular diseases (thromboembolic events within 3 months, NYHA III-IV, ACS within 6 months, or uncontrolled hypertension). 7. Active infection or unexplained fever \> 38.5°C. 8. HIV, active HBV or HCV. 9. Pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | 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). | Defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0) |
| Incidence of dose-limiting toxicities(DLT) | 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） | Observe the dose limiting toxicity, and Incidence of dose-limiting toxicities(DLT) will be assessed |
| Red blood cell count in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Red blood cell count in whole blood |
| White blood cell in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for white blood cell count in whole blood |
| Hematocrit in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Hematocrit in whole blood |
| Neutrophil count in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for neutrophil count in whole blood |
| Hemoglobin concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for hemoglobin concentration in whole blood |
| Percentage of lymphocytes (LYM%) | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Percentage of lymphocytes (LYM%) in whole blood |
| Lymphocyte count | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Lymphocyte count in whole blood |
| Percentage of neutrophils (NEU%) Percentage of neutrophils (NEU%) | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Percentage of neutrophils (NEU%) in whole blood |
| Platelet count in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Platelet count in whole blood |
| Prothrombin time in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Prothrombin time in whole blood sample |
| International normalized ratio in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for international standardized ratio in whole blood sample |
| Fibrinogen in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Fibrinogen in whole blood |
| Activated partial prothrombin time in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for activated partial thromboplastin time in whole blood sample |
| Total bilirubin concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for total bilirubin concentration in whole blood sample |
| ALT concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for alanine aminotransferase(ALT) concentration in whole blood sample |
| AST concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for aspartate aminotransferase(AST) concentration in whole blood sample |
| Total protein concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for total protein concentration in whole blood sample |
| Urea concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for urea concentration in whole blood sample |
| Creatinine concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for creatinine concentration in whole blood sample |
| Total cholesterol concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for total cholesterol concentration in whole blood sample |
| Triglycerides concentration in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for triglycerides concentration in whole blood sample |
| HDL-C in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for high density lipoprotein cholesterol (HDL-C) in whole blood sample |
| LDL-C in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for low density lipoprotein cholesterol (LDL-C) in whole blood sample |
| Glucose in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Lactic dehydrogenase in whole blood |
| Alkaline phosphatase in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Lactic dehydrogenase in whole blood |
| Lactic dehydrogenase in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Lactic dehydrogenase in whole blood |
| Gamma-glutamyl transferase in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Gamma-glutamyl transferase in whole blood |
| Albumin in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Albumin in whole blood |
| Direct bilirubin in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Direct bilirubin in whole blood |
| Sodium in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Sodium in whole blood |
| Potassium in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Potassium in whole blood |
| Chloride in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Chloride in whole blood |
| Calcium in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Calcium in whole blood |
| Phosphate in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Phosphate in whole blood |
| Uric acid in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Uric acid in whole blood |
| Creatine kinase in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Creatine kinase in whole blood |
| Creatine kinase isoenzyme in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Creatine kinase isoenzyme in whole blood |
| Troponin-T (TnT) in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Troponin-T in whole blood |
| Troponin-I (TnI) in whole blood sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Troponin-I in whole blood |
| Urine protein in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Urine protein in urine sample |
| Red blood cells in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Red blood cells in urine sample |
| White blood cells in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for White blood cells in urine sample |
| PH in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for pH in urine sample |
| Ketone bodies in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Ketone bodies in urine sample |
| Urine glucose in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Urine glucose in urine sample |
| Urine bilirubin in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Urine bilirubin in urine sample |
| Urine occult blood in urine sample | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Urine occult blood in urine sample |
| Heart Rate in beats per minute in beats per minute of ECG | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for heart rate in beats per minute |
| RR Interval by ECG | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for RR interval by ECG |
| PR Interval by ECG | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for PR interval by ECG |
| QRS Interval by ECG | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for QRS interval by ECG |
| QT Interval by ECG | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for QT interval by ECG |
| QTcF by ECG | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for QTcF interval by ECG |
| Left ventricular ejection fraction measured by Echocardiography | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Left ventricular ejection fraction measured by Echocardiography |
| Body (Ear) Temperature measurement in Vital Signs | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Body (Ear) Temperature |
| Pulse measurement in Vital Signs | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Pulse |
| Respiration Rate measurement in Vital Signs | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for respiration rate in breaths of Vital Signs |
| Sitting Systolic Blood Pressure | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Sitting Systolic Blood Pressure |
| Sitting Diastolic Blood Pressure | Baseline, Day 1 of each 21-day cycle, and at the End of Treatment (EOT) visit (up to 1 year) | Changes from baseline for Sitting Diastolic Blood Pressure |
| The recommended Phase II dose | After the end of the dose Expansion Phase（only Ic） | Determine the Recommended Phase II Dose(mg/㎡) of HF158K1 and provide references for dose selection in future clinical studies. |
| Determine the maximum tolerated dose | The first administration of the investigational drug to the end of the first treatment cycle, lasting for 21 days. | The dose at which the incidence of DLT was closest to the target probability of toxicity (30%). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HF158K1 pharmacokinetic parameters with Cmax | Within 336 hours after the first and second administration | Maximum plasma concentration (Cmax) after administration of HF158K1 |
| AUC by plasma concentration of whole blood sample | Within 336 hours after the first and second administration | Area under plasma concentration -time curve after dose |
| Tmax by plasma concentration of whole blood sample | Within 336 hours after the first and second administration | Peak time (Tmax) after dose |
| T1/2 by plasma concentration of whole blood sample | Within 336 hours after the first and second administration | Elimination half-life (T1/2) after dose |
| CL by plasma concentration of whole blood sample | Within 336 hours after the first and second administration | Clearance (CL) after dose |
| Vd by plasma concentration of whole blood sample | Within 336 hours after the first and second administration | Volume of distribution(Vd) after dose |
| AUClast by plasma concentration of whole blood sample | Within 336 hours after the first and second administration | Ratios of geometric means of AUClast (Area under the plasma concentration-time curve from zero to time of last quantifiable concentration) after dose |
| The objective response rate(ORR) of HF158K1 | 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. | ORR is defined as the proportion of participants with complete response or partial response (CR+PR) |
| disease control rate (DCR) of HF158K1 | 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. | DCR is defined as the proportion of participants with complete response stable disease and partial response (CR+PR+SD) |
| duration of response(DOR) of HF158K1 | 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. | 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. |
| Analysis of immunogenicity | On the first day of the first cycle, on the first day of the fourth cycle, on the 21st day of the eighth cycle | Immunogenicity analyses related to anti-TL01 antibody will be performed based on IMS(Immunogenicity Analysis Set). |
Countries
China, United States
Contacts
PRINCIPAL_INVESTIGATORMINAL BARVE
Mary Crowley Cancer Research
Outcome results
None listed