A Clinical Study to Investigate the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Preliminary Efficacy of HF158K1 in Participants With HER-2 Positive or HER-2 Low Expression Advanced Solid Tumors

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.

Eligibility Criteria:
Inclusion Criteria:

* 1. Voluntary to participate in the clinical study, sign a written informed consent form, and able to comply with clinical visits and study-related procedures.

  2. Male or female participants at least 18 years old when signing the informed consent form.

  3. ECOG performance score of 0 to 1 point. 4. Study population: HER-2 positive (IHC 3+, or IHC 2+ with ISH +) or HER-2 low expression (IHC 2+ with ISH -, or IHC 1+) participants with unresectable or metastatic advanced solid tumors (confirmed by histopathology or cytology analysis) 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.

  5. Expected survival of at least 3 months. 6. According to the RECIST v1.1 criteria, there is at least one measurable lesion in the dose expansion stage.

  7. The functional level of bone marrow reserve and organs must meet the following requirements (without ongoing continuous supportive treatment): Bone marrow reserve: neutrophil count (NE#) ≥ 1.5×109/L, platelet count (PLT) ≥ 90×109/L, and hemoglobin (HGB) \> 9.0 g/dL (no blood transfusion or hematopoietic stimulating factor therapy within 14 days).

Coagulation function: activated partial prothrombin time (APTT) prolonged to ≤1.5×ULN, and international normalized ratio (INR) ≤1.5.

Liver function: total bilirubin (TBIL) ≤ 1.5×ULN, and alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 2.5×ULN, if there is liver metastasis, ALT and AST ≤ 5×ULN and TBIL≤ 3×ULN.

Renal function: creatinine clearance ≥ 50 mL/min or serum creatinine ≤ 1.5×ULN. 8. Eligible Participants with fertility (male and female) must agree to use reliable contraceptive methods with their partners and have no plan to have baby during the study period and at least 6 months after the last administration. female Participants of childbearing age must have a negative serum or urine pregnancy test during screening period and before the first dose.

9. Other participants that can potentially benefit from the investigational drug as assessed by the investigator.

Exclusion Criteria:

* 1. Participants who are known to be allergic to doxorubicin and/or other similar compounds, or to any of excipients of HF158K1, or participants with allergic constitution (multiple drug and food allergies).

  2. Participants who have used doxorubicin prior to screening with a total cumulative dose \> 350 mg/m2 (other anthracyclines converted by 1 mg doxorubicin equivalence: 2 mg epirubicin, or 2 mg epirubicin, or 2 mg zolpidem, or 0.5 mg demethoxyzolpidem), or who have received anthracyclines and suffered severe cardiotoxicity, or who discontinued doxorubicin liposome therapy due to serious adverse events.

  3. Participants who received radiotherapy or chemotherapy (paclitaxel, cyclosporine, dextropropylenol, cytarabine, streptozotocin, etc.) within 4 weeks prior to first dose administration, or received other antitumor therapy such as endocrine therapy, herbal therapy, or local radiation therapy for pain relief within 2 weeks prior to first dose administration, except for the following: Nitrosourea or mitomycin C within 6 weeks prior to the first administration of the investigational drug.

Oral fluorouracil-based and small-molecule targeted drugs for 2 weeks prior to the first administration of the investigational drug or within 5 half-lives of the drug (whichever is longer).

4. Participants with brain parenchymal metastases or meningeal metastases with clinical symptoms that, in the judgment of the investigator, are not suitable for enrollment (those who have received prior treatment (radiation or surgery) for systemic, radical brain metastases, have maintained imaging- confirmed stability for at least 28 days, and have discontinued systemic steroid therapy for \> 14 days without clinical symptoms will be allowed for enrollment).

5. Participants who have not recovered to \< Grade 1 (according to CTCAE 5.0) or to pre-treatment baseline levels from all prior treatment-induced adverse events prior to the first dose (except for adverse events without safety risks as judged by the investigator, such as alopecia, Grade 2 peripheral neurotoxicity, and stabilized hypothyroidism under hormone replacement therapy).

6. Participants who are taking (or are not able to discontinue until at least 1 week before the first dose of the study) any drug known to strongly inhibit or strongly induce CYP3A4, CYP2D6 or P-gp.

7. Participants with a history of serious cardiovascular and cerebrovascular diseases, including but not limited to: Serious heart rhythm or conduction abnormalities, such as ventricular arrhythmia that requires clinical intervention, degree II-III atrioventricular block, etc.

Cardiac function: left ventricular ejection fraction (LVEF) ≤ 50%, corrected QT interval (QTcF) \> 470 ms.

Thromboembolic events requiring therapeutic anticoagulation within 3 months before the first administration, or participants with venous filters.

Participants with Class III\~IV cardiac insufficiency according to the New York Heart Association (NYHA) criteria.

Acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other Grade 3 and above cardiovascular and cerebrovascular events within 6 months before the first administration.

Clinically uncontrollable hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg), and patients with a history of hypertension were allowed to enroll as long as their blood pressure was controlled below this limitation through antihypertensive therapy.

Any factors that increase the risk of QTc prolongation or arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, or use of any concomitant drug that are known to or may prolong the QT interval.

8. Participants who have received last dose of any other investigational drug product or treatments within 28 days prior to the first administration of the investigational drug.

9. Participants who have undergone major organ surgery (excluding needle biopsy，tracheotomy, gastrostomy, etc.) or had significant trauma within 28 days before the first administration of investigational drug or need to undergo elective surgery during the study period.

10. Participants with a serious unhealable wound/ulcer/fracture within 28 days before the first administration of the investigational drug.

11. Participants with an active infection within 1 week prior to the first administration of the investigational drug and currently require intravenous anti-infection therapy.

12. Third space effusion that cannot be clinically controlled and is not suitable for enrollment as judged by the investigator.

13. Known history of drug abuse. 14. Participants with mental disorders or poor compliance. 15. HIV infection, active HBV infection (HBV DNA \> ULN), or active HCV infection (HCV RNA \> ULN).

16. Women who are pregnant or breastfeeding. 17. Participants who cannot tolerate venous blood sampling. 18. The investigator believes that the participant has a history of other serious systemic diseases or is not suitable for participating in this clinical study for other reasons.