Phase 1/II Clinical Study of SYS6043 in the Treatment of Advanced/Metastatic Solid Tumors

Phase I/II Dose-Escalation, PK Expansion and Cohort Expansion Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of SYS6043 in Patients With Advanced/Metastatic Solid Tumors

Phase I/II Clinical Study of SYS6043 in the Treatment of Advanced/Metastatic Solid Tumors This study is a first-in-human phase I/II, multicenter, open-label, dose-escalation trial with PK expansion and cohort expansion, designed to evaluate the safety, tolerability, pharmacokinetic (PK) profile and preliminary anti-tumor efficacy of SYS6043 (a B7-H3-targeted antibody-drug conjugate) in patients with advanced/metastatic solid tumors. It consists of three parts: dose escalation, PK expansion and cohort expansion.

Inclusion Criteria:

1. Aged 18 to 75 years inclusive (based on the date of signing the informed consent form). For Cohort 2 and Cohort 10, subjects over 75 years of age are eligible for enrollment.

2. Histologically or cytologically confirmed advanced/unresectable or metastatic solid tumors with disease recurrence or progression during or after standard systemic therapy, intolerance to standard therapy, or no available standard therapy.

3. At least one extracranial measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). For participants with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases only, eligibility for enrollment will be determined following a discussion and assessment with the sponsor's medical monitor on a case-by-case basis.

4. Expected survival of the participant is ≥ 3 months.

5. ECOG performance status of 0 or 1 with no deterioration in status identified within 28 days prior to enrollment. For Cohort 2 and Cohort 10, subjects with an ECOG performance status of 2 are eligible for enrollment.

6. Left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiography (ECHO) or radionuclide ventriculography (MUGA) within 28 days prior to enrollment.

7. Adequate function of major organs meeting the following requirements within 7 days prior to enrollment:

   1. Hematology (no receipt of whole blood, red blood cell or platelet transfusion, and no administration of hematopoietic stimulating factors [G-CSF or GM-CSF], erythropoietin [EPO] or thrombopoietin [TPO] for cytorection within 7 days prior to sample collection):Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L;Platelet count (PLT) ≥ 100×10⁹/L;Hemoglobin (HGB) ≥ 90 g/L.
   2. Blood biochemistry:Serum creatinine ≤ 1.5×upper limit of normal (ULN);Serum total bilirubin (TBIL) ≤ 1.5×ULN (may be relaxed to 3×ULN for participants with Gilbert's syndrome);Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN (≤ 5.0×ULN for participants with hepatocellular carcinoma or liver metastases);Serum albumin ≥ 30 g/L.
   3. Coagulation function:Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5×ULN (for participants not receiving anticoagulant therapy); for participants receiving anticoagulant therapy, indices shall be within the therapeutic target range with a stable dosage.

8. Toxic reactions caused by any prior therapy have recovered to ≤ Grade 1 per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 or baseline levels (except for alopecia, fatigue, peripheral neuropathy and other toxicities that the investigator deems to pose no safety risk to the participant).

9. Sufficient washout period for prior anti-tumor therapies before the first study drug administration.

10. Be willing to provide previously resected tumor samples or undergo a fresh tumor biopsy for the detection of B7-H3 expression levels and other biomarkers (if there are no contraindications).

11. For female participants of childbearing potential, the serum pregnancy test result within 7 days prior to randomization must be negative. Male and female participants with reproductive potential must agree to adopt adequate contraceptive measures during the study period and for at least 7 months after the last administration of the study drug; during this period, female participants must not be breastfeeding, male participants must not freeze or donate sperm, and female participants must not donate or retrieve oocytes for personal use.

12. Have a full understanding of this clinical trial and voluntarily sign a written informed consent form

13. Advanced or metastatic solid tumors with failure of standard systemic therapy

Exclusion Criteria:

1. Prior receipt of B7-H3-targeted therapy.
2. Prior receipt of irinotecan, topotecan, any other topoisomerase I inhibitors (including investigational TOP1 inhibitors), or topoisomerase inhibitor antibody-drug conjugates (e.g., trastuzumab deruxtecan). This criterion applies only to the Phase I PK expansion and Phase II cohort expansion stages.
3. A history of symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) or severe cardiac arrhythmias requiring treatment.
4. A history of myocardial infarction or unstable angina within 6 months prior to enrollment.
5. A prolonged corrected mean QT interval (QTcF) using the Fredericia formula of >470 milliseconds (ms) on three 12-lead electrocardiogram (ECG) assessments, for both male and female participants.
6. Inability or unwillingness to discontinue concomitant medications known to prolong the QT interval.
7. A history of interstitial lung disease (ILD)/non-infectious pneumonia requiring glucocorticoid therapy, current ILD/non-infectious pneumonia, or suspected such disease on imaging during screening.
8. A history of underlying pulmonary disease, including but not limited to pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, and other clinically significant pulmonary impairment within 3 months prior to the start of study treatment, or the need for supplemental oxygen.
9. Any autoimmune, connective tissue, or inflammatory disease involving the lungs that is documented or suspected during screening (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.).
10. Uncontrolled infection requiring intravenous antibiotics, antiviral agents, or antifungal agents.
11. Known human immunodeficiency virus (HIV) infection, or currently active syphilis infection (i.e., positive Treponema pallidum antibody [RPR or TRUST] or syphilis requiring systemic therapy).
12. Participants with active viral hepatitis (positive hepatitis B surface antigen [HBsAg] and/or positive hepatitis B core antibody [anti-HBc] with HBV DNA ≥1000 copies/mL or 2000 IU/mL; positive hepatitis C virus [HCV] with HCV RNA above the lower limit of quantification [LLOQ] of the assay).
13. Lactating women (women willing to temporarily discontinue breastfeeding are also excluded), or women confirmed to be pregnant by pregnancy test within 7 days prior to enrollment.
14. Presence of spinal cord compression, or clinically active brain or meningeal metastases. Participants with central nervous system (CNS) metastases are eligible if: they have received prior CNS-directed therapy and have had radiological and neurological stability for at least 4 weeks before the first dose (i.e., no new or enlarging metastatic lesions on imaging, no requirement for corticosteroid therapy or maintenance of a stable or tapering dose of corticosteroids [equivalent to ≤10 mg/day prednisone], and no symptoms); or they have untreated asymptomatic CNS metastases that the investigator assesses as not requiring immediate treatment.
15. A history of multiple primary malignant neoplasms within 3 years prior to enrollment, except for: adequately resected non-melanoma skin cancer (e.g., resected basal or squamous cell skin cancer); in situ disease treated with curative intent (e.g., cervical or breast carcinoma in situ); and other solid tumors treated with curative intent (e.g., superficial bladder cancer).
16. A history of substance abuse, or any other medical condition that the investigator deems may increase the safety risk to the participant or interfere with the participant's participation in or evaluation of the clinical study.
17. Receipt of strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose of the study drug, or the need for continued use of such medications during the study period.
18. Known hypersensitivity to the active ingredient or excipients of the study drug.
19. Presence of pleural, pericardial, or peritoneal effusion with clinical symptoms or requiring repeated drainage.
20. Any other reason that the investigator deems the participant unsuitable for enrollment in the study