This is a Phase I, open-label, multicenter, first-in-human study to evaluate the safety, tolerability, PK/pharmacodynamic (PD) characteristics, and anti-tumor activity of JSKN016HC in subjects with advanced malignant solid tumors.

JSKN016HC is a subcutaneously injectable formulation of a bispecific ADC targeting HER3 and TROP2 (the main active ingredient is JSKN016).

This study will use i3+3 design for dose escalation, with a total of 4-7 dose cohorts designed. The starting dose is 4 mg/kg, Q2W. The dose cohorts and observation periods are defined in the Dose Escalation Table. During the study, necessary adjustments to the escalation dose and dosing interval may be made based on the obtained safety, PK, and other results.

During dose escalation, the SMC will conduct continuous safety assessments. The safety data for each dose cohort must be reviewed and a decision must be made by the SMC before dosing of the next dose cohort can begin. For Dose Cohort 2 (5 mg/kg Q2W), Dose Cohort 4 (7 mg/kg Q2W), and Dose Cohort 6 (9 mg/kg Q2W), the SMC may decide whether to skip these dose cohorts based on a comprehensive consideration of prior safety, PK (if available), and other data.

Inclusion Criteria:

1. Patients who are able to understand the informed consent form (ICF), voluntarily participate, and sign the ICF;

2. Patients who are ≥18 years of age on the day of signing the informed consent form, male or female;

3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1;

4. Life expectancy ≥ 3 months;

5. At least one non-cranial measurable lesion at baseline according to RECIST 1.1 criteria. Target lesions must not have received prior local therapy (e.g., radiotherapy), or there must be evidence of disease progression in the lesion after local therapy;

6. Patients with histologically and/or cytologically confirmed advanced unresectable or metastatic epithelial-derived malignant tumors who have failed prior standard of care (disease progression, intolerance, or inaccessibility of standard of case);

7. Adequate organ function (results from within 7 days before the first dose are required for the following laboratory tests; echocardiogram results from within 28 days before the first dose are acceptable):

   1. Bone marrow function (no whole blood or blood component transfusions within 14 days before the first dose; no use of haematopoietic growth factors within 7 days before the first dose): Absolute neutrophil count ≥1.5×109/L; haemoglobin ≥90 g/L; platelet count ≥100×109/L;
   2. Liver function (based on the normal values of each clinical study site): Total bilirubin ≤ 1.5 × ULN; ALT and AST ≤ 3×ULN (≤ 5×ULN for subjects with metastases to liver); albumin ≥ 28 g/L;
   3. Renal function: Blood creatinine ≤ 1.5 ×ULN, or creatinine clearance (Ccr) ≥ 60 mL/min as calculated by the Cockcroft-Gault formula; urine protein ≤ 1+ or 24-hour (h) quantitative urine protein < 1.0 g;
   4. Coagulation function: International normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN, and activated partial thromboplastin time (APTT) ≤1.5×ULN;
   5. Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% (by echocardiogram);

8. Female patients of childbearing potential or male patients with partners of childbearing potential must agree to use highly effective contraception from the time of signing the ICF until 24 weeks after the last dose. Female patients of childbearing potential must have a negative serum/urine pregnancy test within 7 days before the first dose;

9. Patients who are able and willing to comply with the visits, treatment plan, laboratory tests, and other study-related procedures specified in the protocol.

Exclusion Criteria:

1. Presence of metastasis to brainstem, metastasis to meninges, metastasis to spinal cord or compression, or a history of carcinomatous meningitis; presence of active brain metastasis. Note: a. For patients with brain metastasis previously treated with local therapy (e.g., surgery, radiotherapy): patients who are clinically stable for at least 4 weeks before the first dose (imaging examination shows stable lesions, no new neurological symptoms, no evidence of new or enlarging pre-existing brain metastasis), and have not required corticosteroids or anticonvulsants for at least 2 weeks are eligible for enrollment; b. For patients with brain metastasis not previously treated with local therapy: patients with no neurological symptoms related to brain metastasis, not requiring corticosteroid treatment, no significant oedema around brain metastasis, and with all brain metastases < 1.5 cm are eligible for enrollment;

2. Imaging during the screening period shows the tumor invades or compresses the surrounding vital organs (e.g., heart and pericardium, trachea, oesophagus, superior vena cava, etc.) or risk of developing oesophageal-tracheal fistula or oesophageal-pleural fistula;

3. Insufficient washout period for prior therapies before the first dose:

   1. Receipt of any investigational drug within 28 days before dosing;
   2. Receipt of other anti-tumor therapy within 28 days before dosing or within 5 half-lives of a prior anti-tumor drug (whichever is shorter, but at least 14 days is required);
   3. Receipt of Chinese herbal medicines or proprietary Chinese medicines with a clear anti-tumor indication within 14 days before dosing;
   4. Receipt of non-specific immunomodulatory therapy (e.g., interleukin, interferon, thymosin, tumor necrosis factor, etc.) within 14 days before the first dose;
   5. Requirement for continuous treatment with glucocorticoids (> 10 mg/day prednisone, or equivalent dose of other glucocorticoids) or immunosuppressants for 7 days within 14 days before the first dose; excluding inhaled or topical steroids, or physiological replacement doses of steroids for adrenal insufficiency; short-term (≤7 days) use of glucocorticoids for prophylaxis (e.g., for contrast media allergy) or treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity due to allergen exposure) is permitted;
   6. Receipt of local palliative therapy within 14 days before dosing;
   7. Major surgery within 28 days before dosing (e.g., major abdominal or thoracic surgery; minor procedures such as diagnostic aspiration, infusion device implantation, or biliary stent placement are not included), or anticipation of requiring major surgery during the study;
   8. Receipt of a live vaccine within 30 days before the first dose, or planned receipt of a live vaccine during the study;

4. Prior treatment with an ADC containing a topoisomerase I inhibitor (e.g., DS-8201, HER3-DXd, DS-1062, etc);

5. Concurrent other malignant tumor within 5 years before dosing, excluding cured cutaneous squamous cell carcinoma, basal cell carcinoma, non-muscle invasive bladder cancer, and in situ prostate/cervical/breast cancer/ papillary thyroid carcinoma, etc;

6. Presence or history of the following lung disorders that cause severe impairment of respiratory function:

   1. Active or severe structural lung disorder: including pulmonary embolism diagnosed within 6 months before the first dose, uncontrolled severe asthma (e.g., requiring continuous systemic steroid therapy or frequent acute exacerbations), severe chronic obstructive pulmonary disease, or severe restrictive pulmonary disease (e.g., severe pulmonary fibrosis, deformity thorax), etc.;
   2. Systemic diseases with pulmonary involvement: autoimmune diseases, connective tissue diseases, or inflammatory diseases (e.g., rheumatoid arthritis, sicca syndrome, sarcoidosis, etc.) causing significant impairment of respiratory function;
   3. Pulmonary resection: prior pneumonectomy;

7. Current interstitial lung disease (ILD) or non-infectious pneumonia (e.g., idiopathic pulmonary fibrosis, radiation pneumonitis, etc.) requiring systemic glucocorticoid or other immunosuppressant therapy;

8. Clinically significant gastrointestinal abnormalities, including but not limited to:

   1. Intestinal obstruction or signs and symptoms of intestinal obstruction within 6 months before the first dose, but screening is permissible if surgery has been performed and the obstruction is completely resolved (patients who have previously received an intestinal stent that has not been removed by the screening period are not allowed to enroll);
   2. History of gastrointestinal perforation, intestinal fistula, intra-abdominal abscess, and non-gastrointestinal fistula (e.g., oesophageal-tracheal fistula) within 6 months before the first dose;
   3. Gastrointestinal haemorrhage of ≥ Grade 3 (CTCAE v5.0) within 6 months before the first dose, or gastrointestinal haemorrhage within 1 month (including melaena, haematochezia, etc.; patients confirmed to have haemorrhoidal haemorrhage or only presenting with faecal occult blood positive are eligible for enrollment);

9. Active autoimmune disease requiring systemic treatment within the past two years (e.g., treatment with disease-modifying drugs, corticosteroids, immunosuppressants). Note: Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a systemic treatment;

10. Presence of serous cavity effusion (e.g., pleural effusion, pericardial effusion, ascites) that is clinically symptomatic or requires repeated drainage(>1 time/week), or has required drainage within 14 days before the first dose;

11. Presence of any of the following cardiovascular or cerebrovascular disorders or risk factors:

    1. Myocardial infarction, unstable angina, acute or persistent myocardial ischaemia, Grade ≥3 cardiac failure (NYHA classification), symptomatic or poorly controlled severe arrhythmia (e.g., ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, complete left or right bundle branch block, history of second- or third-degree heart block, etc.), cerebrovascular accident, transient ischaemic attack, or other severe cardiovascular or cerebrovascular disorders within 6 months before the first dose;
    2. Any arterial thromboembolic event or venous thromboembolic event of ≥ Grade 3 (CTCAE v5.0) within 6 months before the first dose;
    3. Presence of major vascular diseases that may be life-threatening or require surgery within 6 months, such as aortic aneurysm, aortic dissection, or severe internal carotid artery stenosis;
    4. Risk of QT interval prolongation or severe arrhythmia, including baseline QT interval corrected by Fridericia's formula (QTcF) > 470 ms, refractory hypokalaemia, long QT syndrome, etc.;
    5. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg);
    6. Presence of moderate to severe pulmonary arterial hypertension;

12. Uncontrolled infection, including but not limited to the following:

    1. Active HBV or HCV infection. HBsAg-positive patients are required to undergo HBV-DNA testing; if HBV-DNA is above the lower limit of detection of the local laboratory, they will be excluded. For HBsAg-positive patients, enrollment is permitted if HBV-DNA is below the lower limit of detection after receiving antiviral therapy, and anti-HBV therapy should be continued after subsequent treatment. HCV-Ab-positive patients are eligible for enrollment if HCV-RNA test is negative;
    2. Severe infection within 4 weeks before the first dose, including but not limited to comorbidities requiring hospitalisation, sepsis, or severe pneumonia; active infection requiring systemic anti-infective drug therapy within 2 weeks before the first dose;
    3. History of immunodeficiency, positive test for human immunodeficiency virus (HIV), or history of acquired immunodeficiency syndrome (AIDS);
    4. Known active tuberculosis;
    5. Active syphilis;

13. Toxicity from prior anti-tumor therapy has not resolved to ≤ Grade 1 (CTCAE v5.0) or the level specified in the inclusion/exclusion criteria. Note: Patients with chronic, stable Grade 2 toxicity that the investigator considers related to prior anti-tumor therapy may be enrolled after discussion with the sponsor and medical monitor (defined as stable toxicity severity, CTCAE Grade ≤2, within 3 months before the first dose), such as: chemotherapy-induced neurotoxicity, alopecia, skin hyperpigmentation, fatigue, endocrine toxicity from prior immunotherapy (e.g., thyroid dysfunction, diabetes mellitus, adrenal insufficiency);

14. History of prior allogeneic bone marrow or organ transplant;

15. Known hypersensitivity to any component of the investigational product; history of severe allergic reactions to other antibody-based drugs;

16. History of severe xerophthalmia, severe meibomian gland disease and/or blepharitis, keratopathy causing incurable or delayed healing of the subject's cornea, or maculopathy;

17. Women who are pregnant and/or breastfeeding, or who plan to become pregnant during the study;

18. Known history of psychiatric illness, drug abuse, alcoholism, etc., or other conditions that, in the investigator's opinion, would interfere with the safety or compliance of drug therapy in this study;

19. Prior or current presence of any other disease, treatment, or abnormal laboratory test that might confound the study results, interfere with the subject's full participation in the study, or for which participation in the study might not be in the subject's best interest;

20. Presence of local or systemic diseases caused by non-malignant tumor, or diseases or symptoms secondary to the tumor, which may lead to higher medical risk and/or uncertainty in survival assessment, such as tumor-related leukaemoid reaction (white blood cell count >20×109/L), cachexia, etc.