Study of IBI354 Versus Investigator's Choice of Chemotherapy in Patients With Platinum-resistant Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Inclusion Criteria

1. Have signed the informed consent form (ICF) and are able to comply with the follow-up visits and related procedures required in the protocol.
2. Female subjects, aged ≥ 18 years.
3. Life expectancy ≥ 12 weeks.
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
5. Histologically or cytologically confirmed locally advanced unresectable or metastatic ovarian cancer, primary peritoneal cancer, or fallopian tube cancer:

   1. HER2 expression (IHC1+, IHC2+, IHC 3+) in tumor tissues confirmed by the HER2 expression testing performed by the sponsor's designated central laboratory (hereinafter referred to as the central laboratory).Note: Subjects must provide a sufficient tumor tissue sample for central HER2 assessment.Freshly collected biopsy samples are preferred, and formalin-fixed and paraffin-embedded (FFPE) blocks are preferred.If a newly collected biopsy cannot be provided, the most recent archival sample will be required.If the subjects have previously been confirmed by the central laboratory to have HER2 expression in tumor tissues (IHC1+, IHC2+, IHC 3+), they meet the inclusion criteria and do not need to be retested.
   2. Previously received ≥ 1 line of platinum-based chemotherapy and experienced disease progression: If only received 1 line of platinum-based chemotherapy, they must have received at least 4 cycles of platinum-based therapy, have a best response of PR or CR (not required for adjuvant therapy), and have experienced disease progression \> 3 months and \< 6 months after the last platinum-based chemotherapy; if received 2 or more lines of platinum-based chemotherapy, they must have experienced disease progression during or \< 6 months after the last platinum-based chemotherapy.Note: Progressive disease is progressive disease shown by imaging as per RECIST v1.1.
   3. Patients must have received at least 1 line of prior systemic anti-tumor therapy:

      * Adjuvant ± neoadjuvant therapy is considered as 1 line of systemic anti-tumor treatment.
      * Maintenance therapy \[e.g., bevacizumab, poly adenosine diphosphate-ribose polymerase (PARP) inhibitor\] as part of front-line anti-tumor therapy (the number of lines will not be calculated separately).
      * For a change in treatment regimen, if the changed treatment drug is the same type of drug as the previous first-line treatment (e.g., platinum, taxane, anthracycline, PARP inhibitor, etc. before and after the change), and there is no disease progression before the change in treatment drug, the changed treatment regimen will be used as part of the number of lines of previous treatment and will not be counted separately.If the changed therapeutic drug is a different type of drug from the previous first-line treatment, or if the drug of the same type is changed after disease progression, the number of lines should be calculated separately.
      * If anti-tumor drugs are added to the original treatment regimen for combination therapy (except for maintenance treatment), the number of lines should be calculated separately.
      * The number of lines of endocrine therapy will be calculated separately unless administered as a maintenance regimen.
   4. For subjects with documented positive expression of folate receptor α (FRα) in tumor tissues \[using the VENTANA FOLR1 (FOLR-2.1) RxDx assay to assess the percentage of tumor cells with moderate (grade 2) and/or strong (grade 3) membrane staining to the total number of viable tumor cells ≥ 75% based on the "PS2+" scoring method\], prior treatment with mirvetuximab soravtansine (MIRV) or an ADC drug with the same target and radiographically confirmed progressive disease as per RECIST v1.1 is required.
   5. Subjects with documented BRCA mutations (germline and/or somatic) must have received prior treatment with a PARP inhibitor.This study allowed the inclusion of subjects with BRCA mutations identified during the platinum-resistant phase who were PARP inhibitor-naïve.
6. Patients must have radiologically confirmed disease progression according to RECIST v1.1 during or after the most recent line of anti-tumor therapy.
7. At least 1 measurable target lesion according to RECIST v1.1 \[long diameter ≥ 10 mm (short diameter ≥ 15 mm for lymph node lesions) as accurately measured by computed tomography (CT) or magnetic resonance imaging (MRI, with intravenous contrast agent preferred) at baseline, and the lesion is suitable for repeated and accurate measurements\].Lesions that have received prior local treatment (e.g., radiotherapy, radioactive seed implantation, and hepatic artery embolization/infusion chemotherapy) can be considered measurable target lesions only if they clearly show PD as per RECIST v1.1\].
8. Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days prior to the first dose of the investigational drug.
9. Adequate bone marrow and organ functions, with laboratory test values meeting the following requirements within 7 days before the first dose of the study drug (If the laboratory tests performed during the screening period do not meet the requirements below, only 1 retest is allowed during the screening period.Any cell/blood component, colony stimulating factor, or cytokine therapy is not allowed within 7 days prior to the hematology test):

   1. Routine blood test: absolute neutrophil count (ANC) ≥ 1.5 × 109/L or within the normal range; platelet count (PLT) ≥ 90 × 109/L; hemoglobin (HGB) ≥ 90 g/L.
   2. Liver function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); for subjects with Gilbert's syndrome, TBIL ≤ 3 × ULN; for subjects without liver metastasis, AST and ALT ≤ 2.5 × ULN; for subjects with liver metastasis, AST and ALT ≤ 5 × ULN, TBIL ≤ 3 × ULN; albumin (ALB) ≥ 28 g/L.
   3. Renal function: serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 mL/min (calculated using the Cockcroft-Gault formula or by measuring the volume of 24-h urine collection); urinalysis indicates urine protein \< 2+, and for subjects whose baseline urinalysis indicates urine protein ≥ 2+, 24-h urine collection should be performed and the protein content in 24-h urine should be \< 1 g (if both test methods are adopted, the measured value from 24-h urine collection will be used to determine eligibility).
   4. Coagulation function: International Normalized Ratio (INR) ≤ 1.5; activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.
10. For female subjects of childbearing potential, effective contraceptive measures are required throughout the treatment period and 6 months after the treatment period (see Section5.8.1.1).

Exclusion Criteria

Subjects should not be enrolled in the study if they meet any of the following criteria:

1. Histological or cytological examination results meet any of the following conditions:

   1. Documented sarcoma, mucinous carcinoma, undifferentiated carcinoma, or a combination.
   2. Demonstrated low-grade or borderline tumors, or both.
2. Participation in any other interventional clinical study, except for observational (non-interventional) studies or follow-up period after the end of study treatment in interventional studies.
3. Paclitaxel, gemcitabine, liposomal doxorubicin, and topotecan listed in the control arm are not suitable (e.g., all of the above drugs have been previously treated, without any disease response, and with disease progression within 6 months after the last dose).
4. Prior treatment with ADC drugs with a small molecule payload of camptothecin or its derivatives.
5. Prior to the first dose of study drug:

   1. Received systemic treatment such as intravenous infusion of chemotherapy drugs, large molecule targeted drugs, antibody-drug conjugates, immunotherapy, endocrine therapy, or cell therapy within 4 weeks; received local treatment such as intraperitoneal perfusion chemotherapy, tumor embolization, or interventional chemotherapy within 2 weeks.
   2. Received oral chemotherapy drugs, small molecule targeted drugs, and Chinese herbal medicines indicated for anti-tumor treatment within 2 weeks or 5 half-lives (whichever is longer).
   3. Radical radiotherapy within 4 weeks; palliative radiotherapy within 2 weeks.
   4. Treatment with strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) within 2 weeks or 5 half-lives (whichever is longer).
   5. Major surgery (craniotomy, thoracotomy or laparotomy, and other types considered by the investigator to be "major", excluding needle biopsy) within 4 weeks, or presence of significant unhealed wounds, trauma, or ulcers; exploratory laparoscopy within 2 weeks.
   6. Live(mRNA and non-replicating adenovirus vaccines are not considered live)vaccines within 4 weeks.
6. Patients with adverse reactions caused by previous anti-tumor treatments that have not been alleviated to grade 0 or 1 before enrollment according to NCI-CTCAE v5.0 criteria \[except for grade 2 alopecia, asthenia, pigmentation, insomnia, peripheral neuropathy, hypomagnesemia, and toxicities stably controlled by medication (such as hypothyroidism stably controlled by replacement therapy, and hypertension stably controlled below 160/100 mmHg after antihypertensive medication).
7. Symptomatic central nervous system (CNS) metastasis, spinal cord compression, carcinomatous meningitis, or history of leptomeningeal carcinoma.Subjects with asymptomatic CNS metastases (no neurological symptoms, no need for corticosteroid treatment, and the diameter of metastases is ≤ 1.5 cm) or subjects with brain metastases that are stable after treatment may be considered for inclusion in the study if they meet all of the following criteria: (1) measurable lesions outside the central nervous system; (2) no metastases to midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord; (3) stable for at least 4 weeks, without new or enlarging metastases (Clinical symptoms, signs, andRadiologic evidence clearly confirmed); (4) Corticosteroids or anticonvulsants were discontinued at least 2 weeks prior to the first dose of study drug.Central nervous system lesions should be monitored and examined regularly during the study.

   Note:Central nervous system lesions will not be considered target lesions.
8. Subjects with pneumonia requiring corticosteroid therapy, or uncontrolled lung diseases (e.g., pulmonary fibrosis, severe radiation pneumonia, and acute lung injury) or suspected to have such diseases by imaging during the screening period.
9. Uncontrolled or significant cardiovascular and cerebrovascular diseases, including the following conditions:

   1. Uncontrolled myocarditis, or symptomatic congestive heart failure Class II-IV (New York Heart Association \[NYHA\] criteria), symptomatic or uncontrolled arrhythmias such as ventricular tachycardia, atrial fibrillation, ventricular fibrillation, torsades de pointes, etc.
   2. Fridericia-corrected QT interval (QTcF) \>480 ms, personal or family history of congenital long/short QT syndrome.If QTcF is \> 480 ms in 1 ECG examination during the screening period, 3 consecutive ECG examinations are required to calculate the mean QTcF value. If QTcF is still \> 480 ms, the subject will not be enrolled.
   3. Before the first dose of study treatmentHistory of any arterial thromboembolic events within 6 months, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
   4. History of deep vein thrombosis, pulmonary embolism, or any other serious thromboembolic event within 3 months prior to first dose of study intervention.Patients who have received anticoagulant therapy for 2 weeks after the discovery of deep vein thrombosis and have stable thrombosis after re-examination, or have a low risk (such as intermuscular venous thrombosis) as assessed by the investigator, are considered to meet the inclusion criteria.
   5. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) despite of standard treatment.
10. Received immunosuppressants within 14 days prior to the first dose of study treatment, excluding intranasal and inhaled corticosteroids, or systemic corticosteroids at doses lower than 10 mg/day of prednisone (or equivalent), or corticosteroids for preventing allergy to contrast media.
11. Tumor invades surrounding important tissues and organs, accompanied by obvious clinical symptoms or abnormal organ functions (such as mediastinal great vessels, superior vena cava and inferior vena cava, pericardium, heart, trachea, etc.).
12. Bleeding within 3 months prior to the first start of study treatment that is life-threatening, requiring blood transfusion or invasive treatment.
13. Symptomatic abdominopelvic effusion requiring intervention (except abdominopelvic effusion caused by tumor as judged by the investigator), pleural effusion, or pericardial effusion (subjects with stably controlled effusion are allowed to be enrolled, defined as no significant increase in effusion under the condition of removing the drainage tube or no drainage, and no clinical symptoms, for at least 7 days).
14. Subjects with esophageal or gastric varices requiring immediate intervention (e.g., ligation or sclerotherapy), or who are considered by the investigator or gastroenterology and hepatology experts to be at high risk for bleeding, have evidence of portal hypertension (including splenomegaly from imaging) or have a history of variceal bleeding, must undergo endoscopic assessment within 3 months prior to the first start of study treatment.
15. Patients with unhealed gastrointestinal obstruction, perforation, or fistula, or at risk of gastrointestinal obstruction or perforation (including but not limited to acute diverticulitis and abdominal abscess), or with a history of extensive bowel resection (e.g., extensive small bowel resection accompanied by chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.Note: The digestive tract refers to the muscular tube from the oral cavity to the anal canal, including the oral cavity, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, and ileum), large intestine (cecum, appendix, colon, and rectum), and anal canal.
16. After tracheal stent implantation; after gastrointestinal stent implantation, the subject did not resume normal diet or defecation.
17. Subjects with biliary obstruction, unless the obstruction has been treated locally (e.g., endoscopic stenting or percutaneous transhepatic drainage), and TBIL has decreased to \< 1.5 × ULN.
18. Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh Class B or above.
19. Significant malnutrition, such as malnutrition requiring intravenous nutrition.Except for patients who have resumed a normal diet prior to the first study treatment and have discontinued intravenous nutrition.
20. Active uncontrolled infection, including the following:

    1. Infection requiring systemic antibiotic, antiviral, or antifungal therapy.
    2. Human immunodeficiency virus (HIV) infection (HIV 1/2 Ab positive).
    3. Acute or chronic active hepatitis B, defined as hepatitis B surface antigen or e antigen positive (any other antibody result) or hepatitis B core antibody positive only (hepatitis B surface antibody negative and hepatitis B e antibody negative), and HBV DNA copy number ≥ 1 × 104Copy number/mL or ≥ 2000 IU/mL; or acute or chronic active hepatitis C, defined as hepatitis C virus (HCV) antibody positive and HCV RNA titer above the lower limit of detection.
    4. Active tuberculosis infection, or still receiving anti-tuberculosis treatment, or received anti-tuberculosis treatment within 1 year before the first dose of the study drug.
21. Complicated with other primary malignancies or other malignancies with active or recurrent risks within 3 years prior to the first dose of study treatment, excluding radically treated basal cell carcinoma of skin, squamous cell carcinoma of skin, radically resected carcinoma in situ, and papillary thyroid carcinoma.
22. History of immunodeficiency diseases, including congenital or acquired immunodeficiency diseases.
23. History of allogeneic organ transplantation, allogeneic bone marrow transplantation, or autologous hematopoietic stem cell transplantation (except corneal transplantation).
24. Allergic to other anti-HER2 antibodies/ADCs, camptothecins and their derivatives, or any component of IBI354.
25. Subjects who are pregnant or breastfeeding (may be considered if breastfeeding is discontinued), or subjects who plan to become pregnant.
26. Presence of other acute or chronic diseases or laboratory abnormalities that may increase the risk of study participation or drug administration, interfere with the interpretation of study results, or render the subjects unsuitable for participating in the study as judged by the investigator.
27. Subject has a neurologic, psychiatric, or social condition that would interfere with trial compliance, significantly increase the risk of adverse events, or prevent the subject from providing written informed consent.