A Study of SYS6043 in Platinum-Resistant, Advanced Ovarian, Primary Peritoneal, or Fallopian Tube Cancers

Prior treatment

• Prior treatment with B7H3-targeted therapy.
• Prior treatment with irinotecan, topotecan, any other topoisomerase I inhibitor (including investigational TOP1 inhibitors), or topoisomerase inhibitor-antibody drug conjugate (e.g., trastuzumab deruxtecan, etc.).
• History of severe cardiac or cerebrovascular disease, including but not limited to: heart failure ≥ New York Heart Association (NYHA) Class 2; acute coronary syndrome (e.g., myocardial infarction, unstable angina, etc.) within 6 months prior to screening; acute cerebrovascular disease (e.g., transient ischemic attack, cerebral infarction, cerebral hemorrhage, etc.) within 6 months prior to screening.
• A history of underlying lung diseases, including but not limited to pulmonary embolism within 3 months prior to the start of study treatment, severe asthma, severe COPD, restrictive lung disease, and other clinically significant lung damage or requiring supplementary oxygen.
• Patients with active pulmonary tuberculosis (those who have received adequate treatment and stopped anti-tuberculosis treatment for ≥ 3 months before randomization may be enrolled).
• Unstable thrombotic events requiring therapeutic intervention within 6 months prior to screening, such as deep vein thrombosis, arterial thrombosis, and pulmonary embolism (patients with stable lower extremity deep vein thrombosis, intermuscular venous thrombosis, or infusion-related thrombosis that are judged to be risk-free by the investigator may be included).
• Presence of spinal cord compression or clinically active brain metastasis or meningeal metastasis. Participants with central nervous system metastases who have received prior central nervous system-directed therapy and have been radiologically and neurologically stable within 4 weeks before the first dose \[i.e., imaging shows no new or enlarged metastatic lesions, no need for corticosteroid treatment or taking a stable or decreasing dose of corticosteroids (equivalent to ≤ 10 mg/day prednisone), and no symptoms\] are eligible to enter the study. Untreated central nervous system metastases may be enrolled if the following conditions are met: no neurological symptoms, no need for surgery, radiotherapy, or corticosteroid treatment, and no obvious edema around the brain metastases.
• Diagnosis of active malignant tumor within 3 years prior to randomization, except for the following cases: cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, and/or carcinoma in situ that has undergone radical resection, which the investigator deems eligible for enrollment.
• Presence of intestinal obstruction, or signs and symptoms of intestinal obstruction, or requiring parenteral nutrition within 1 month prior to the start of study treatment; however, screening may be performed if surgical treatment has been performed and the obstruction is completely relieved; prior intestinal stent implantation with the intestinal stent still not removed by the screening period; gastrointestinal bleeding (including melena, hematochezia, etc.) within 1 month prior to randomization (those confirmed to have hemorrhoidal bleeding or only positive fecal occult blood may be enrolled); presence of abdominal abscess within 1 month prior to randomization.
• Subjects who have received systemic administration of strong inhibitors or strong inducers of CYP3A4 and CYP2C8, or inhibitors of OATP1B1/OATP1B3 within 14 days prior to the first dose of study drug, or those who require continuous systemic use of such medicinal products during the study period.
• Having undergone autologous or allogeneic stem cell transplantation.
• Subjects planning to receive live vaccines or vaccinated with live vaccines within 28 days before the first dose of study drug.

Other illness

• Patients with platinum-refractory disease (progression within 1 month after the last platinum-containing therapy).
• A history of or current interstitial lung disease (ILD) requiring glucocorticoid treatment, non-infectious interstitial pneumonia, pulmonary fibrosis, and radiation pneumonitis requiring hormone treatment, or suspected of having such diseases by imaging examination at the time of screening.
• Any autoimmune disease, connective tissue disease, or inflammatory disease involving the lungs that is recorded or suspected at the time of screening (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.).
• Presence of uncontrolled infection requiring intravenous antibiotics, antiviral drugs, or antifungal drugs.
• Known human immunodeficiency virus (HIV) infection, or current active syphilis infection (i.e., positive treponema pallidum antibody (RPR or TRUST) or requiring systemic treatment).
• Participants with active viral hepatitis (positive hepatitis B surface antigen and/or positive hepatitis B core antibody with HBV DNA ≥ 10000 copies/ml or 2000 IU/ml; positive hepatitis C virus (HCV) with HCV RNA above the lower limit of detection by the analytical method).
• Presence of fistula diseases and perforation diseases such as genital fistula, genitourinary fistula, and enterovaginal fistula (if the perforation or fistula has been treated by resection or repair and the disease has recovered, enrollment is allowed).
• Known allergy to the active ingredient or excipients of the study drug.
• Subjects with a history of severe neurological or psychiatric disorders, including but not limited to dementia, depressive disorder, epileptic seizure, and bipolar disorder.
• Have a history of drug abuse, or have any other medical conditions that, in the opinion of the Investigator, may increase the safety risk to the participant, or interfere with the participant's enrollment in and completion of the clinical study, or confound the evaluation of the study results.

Lab values

• Mean corrected QT interval using the Fridericia formula (QTcF) \> 470 milliseconds (ms) based on the results of three 12-lead electrocardiogram (ECG) examinations; history of serious cardiac arrhythmia (e.g., complete left bundle branch block, third-degree atrioventricular block, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, etc.), excluding transient atrial fibrillation and atrial flutter.
• Unable or unwilling to discontinue concomitant medications known to prolong the QT interval.
• Subjects with other severe physical conditions, clinically significant laboratory abnormalities, or poor treatment compliance, who may increase the risks of study participation, interfere with study outcomes, or are otherwise considered unsuitable for enrollment in this study by the Investigator.

Other

• Patients for whom paclitaxel, topotecan, and pegylated liposomal doxorubicin (as listed in the control group) are all considered inappropriate by the investigator.
• Moderate or above pleural effusion, pericardial effusion, or ascites; if effusion drainage is performed (except for diagnostic thoracentesis), participants who have been stable for at least 2 weeks after drainage may be enrolled.

• Female participants aged ≥ 18 years (as of the date of signed informed consent).
• Histologically or cytologically confirmed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with a histologic subtype of high-grade serous carcinoma or G2-G3 endometrioid carcinoma.
• Participants with prior platinum-based therapy and confirmed platinum-resistant recurrent disease, defined as disease progression or recurrence during platinum-based chemotherapy or within 6 months (183 days) after the last dose of platinum-based chemotherapy. A total number of treatment lines not exceeding 5 lines.
• At least one evaluable extracranial lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
• Expected survival of the participant is ≥ 3 months. 5.6. For patients with previously confirmed folate receptor-α (FRα) positivity (verified by Ventana FOLR-2.1 assay: ≥75% of tumor cells exhibiting moderate \[2+\] or strong \[3+\] staining intensity per the PS2+ scoring method), prior treatment with mirvetuximab soravtansine is required, unless the investigator deems the patient intolerant to mirvetuximab soravtansine or the patient is ineligible for this therapy per the warnings in the prescribing information.
  • 6.7. ECOG performance status 0-1, with no deterioration in ECOG score within 28 days prior to enrollment.
  • 7.8. LVEF ≥ 50% as demonstrated by ECHO or MUGA obtained within 28 days before enrollment.
  • 8.9. Major organ function must meet the following criteria within 7 days prior to enrollment:
• Complete blood count (no whole blood, red blood cell, or platelet transfusion, and no administration of hematopoietic growth factors \[G-CSF or GM-CSF\], erythropoietin \[EPO\], or thrombopoietin \[TPO\] to correct blood cell counts within 7 days before sampling):i. Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L;Platelet count (PLT) ≥ 100 × 10\^9/L;Hemoglobin (HGB) ≥ 90 g/L.
• Blood biochemistry:i. Serum creatinine ≤ 1.5 × ULN;Serum total bilirubin (TBIL) ≤ 1.5 × ULN (participants with Gilbert's syndrome may be allowed up to 3 × ULN);Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5.0 × ULN for participants with hepatocellular carcinoma or liver metastasis);Serum albumin ≥ 30 g/L.
  • 3\) Coagulation function: i. Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN (for participants not receiving anticoagulation therapy; for those on anticoagulation therapy, levels must be within the therapeutic range with stable dose).
  • 10\. Any toxicities related to prior therapy have resolved to CTCAE version 6.0 grade ≤1 or baseline level, excluding alopecia, fatigue, pigmentation, hypothyroidism stabilized with hormone replacement therapy, grade 2 peripheral neuropathy following chemotherapy, and other toxicities that the investigator deems not to pose a safety risk to participants.
  • 11\. A sufficient washout period from prior anti-tumor therapy is required prior to the first study drug administration.
  • 12\. Willing to provide a previously excised tumor sample or undergo a fresh tumor biopsy for the assessment of B7-H3 expression level (if no contraindications exist).
  • 13\. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.Female participants of childbearing potential must agree to use highly effective contraception during the study and for at least 7 months after the last dose of study drug.Females must not be breastfeeding during this period.Females must not donate oocytes or undergo oocyte retrieval for personal use during this period.
  • 14\. Provides voluntary written informed consent after adequate understanding of the clinical trial.