A Study of SKB518 as Monotherapy or Combination Therapy in Patients With Advanced Gynecological Malignant Tumors

An Open-label, Multicenter, Phase II Clinical Study to Evaluate the Efficacy and Safety of SKB518 as Monotherapy or Combination Therapy in Patients With Advanced Gynecological Malignancies

This is an open-label, multicenter, Phase II clinical study to evaluate the efficacy and safety of SKB518 as monotherapy or combination therapy in patients with advanced gynecological malignancies.

This study will include 5 cohorts: SKB518 as monotherapy in advanced ovarian cancer; SKB518 as monotherapy in advanced cervical cancer and endometrial cancer; SKB518 in combination with Carboplatin in advanced ovarian cancer; SKB518 in combination with Carboplatin and Bevacizumab in advanced ovarian cancer; and SKB518 in combination with Bevacizumab in advanced ovarian cancer.

Study hypothesis: SKB518 will show meaningful clinical activity and a favorable risk benefit profile in gynecological malignancies.

Inclusion Criteria:

1. Provide signed written informed consent and demonstrate understanding of and agreement to comply with study requirements and the study visit schedule.

   Age

2. Be ≥ 18 years and ≤ 75 years of age at the time of informed consent signing.

   Participant Type and Disease Characteristics

3. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 within 2 weeks prior to first dose administration.

4. Have a cytologically or histologically confirmed gynecologic malignancy.

   • Cohort A: Ovarian cancer (OC) (including fallopian tube cancer and primary peritoneal cancer) with epithelial ovarian carcinoma histology, previously treated with 2-4 lines of systemic therapy, excluding primary platinum-resistant ovarian cancer (defined as disease recurrence or progression during first-line platinum-containing therapy, or disease recurrence or progression occurring <182 days from the last platinum-containing therapy in the first line).
   • Cohort B: Cervical cancer or endometrial cancer that has failed standard therapy or is intolerant to standard therapy, or for which no standard therapy exists.
   • Cohort C: Platinum-sensitive ovarian cancer (PSOC) previously treated with 2-4 lines of systemic therapy.
   • Cohort D: PSOC previously treated with 1-2 lines of systemic therapy.
   • Cohort E Safety Lead-in Phase: PSOC previously treated with 2-4 lines of systemic therapy.
   • Cohort E Expansion Phase: PSOC participants who have achieved Complete Response (CR),Partial Response (PR), or Stable Disease (SD) after 2 lines of therapy (platinum-based doublet regimen combined with bevacizumab), and require randomization within 8 weeks after the last dose.

   Participants in Cohorts A, C, D, and E with known breast cancer susceptibility gene (BRCA) mutations must have received poly(ADP-ribose) polymerase (PARP) inhibitor therapy, unless contraindicated.

   Note:

   1. PSOC is defined as radiographic progression/recurrence occurring ≥6 months after the last platinum-containing chemotherapy, i.e., the interval from the date of the last platinum therapy to radiographic evidence of disease progression per RECIST v1.1 should be ≥6 months (182 days).

   2. Line counting rules for OC are as follows:

      • Adjuvant ± neoadjuvant therapy is considered 1 line of systemic antineoplastic therapy.
      • Maintenance therapy (e.g., bevacizumab, PARP inhibitors) as part of frontline antineoplastic therapy is not counted as a separate line.
      • Treatment regimen changes due to intolerance toxicity rather than disease progression are considered part of the same prior treatment line and are not counted as a separate line.

5. Provide approximately 10-13 unstained consecutive tumor tissue slides during the screening period for gene expression level testing (preferably from recently obtained tissue). If fresh tumor tissue samples are unavailable, archived tumor tissue samples obtained within 2 years prior to first study dose administration may be provided. If a participant is unable to provide archived tumor tissue samples within 2 years prior to first dose, or unable to provide a sufficient number of unstained consecutive tumor tissue slides, the investigator must discuss with the medical monitor to determine whether earlier obtained tumor tissue samples or a reduced number of slides may be accepted. Fine-needle aspiration biopsy specimens or core biopsies are insufficient for biomarker testing. Cell smears from centrifuged thoracic/abdominal/pelvic/pericardial effusion drainage, and bone lesions without soft tissue components or from decalcified bone tumor specimens are also unacceptable.

6. Have at least one target lesion per RECIST v1.1 criteria, accurately measured at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) (intravenous contrast preferred) with a longest diameter ≥10 mm (except for lymph nodes, which must have a short axis ≥15 mm), and the lesion must be suitable for repeated accurate measurement. Lesions located in previously irradiated areas or that have undergone biopsy may serve as measurable target lesions if there is documented evidence of disease progression per RECIST v1.1. Brain lesions are not considered target lesions.

7. Have an estimated life expectancy ≥12 weeks as assessed by the investigator.

8. Demonstrate adequate bone marrow, hepatic, renal, and coagulation function based on laboratory tests performed within 7 days prior to first dose (hematology tests required within 3 days prior to first dose) [supportive treatments, including transfusions, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), thrombopoietin (TPO), TPO receptor agonists (TPO-RA), and interleukins, are not permitted within 14 days prior to first dose]:

   1. Hematology: Absolute neutrophil count (NEUT) ≥1.5×10⁹/L; Platelet count (PLT) ≥100×10⁹/L; Hemoglobin (Hb) ≥90 g/L;
   2. Hepatic function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×upper limit of normal (ULN); for participants with hepatic metastases, ALT and AST ≤5×ULN; Total bilirubin (TBIL) ≤1.5×ULN and direct bilirubin (DBIL) ≤1.5×ULN;
   3. Renal function: Serum creatinine (Cr) ≤1.5×ULN, or calculated creatinine clearance ≥60 mL/min using the Cockcroft-Gault formula (see Appendix 4); Urinalysis indicating urine protein <2+; for participants with urine protein ≥2+ on baseline urinalysis, a 24-hour urine collection should be performed with protein content <1 g in 24 hours (if both testing methods are used, the 24-hour urine collection value will be used to determine eligibility);
   4. Coagulation function: International normalized ratio (INR) ≤1.5; Activated partial thromboplastin time (aPTT) and prothrombin time (PT) ≤1.5×ULN.

9. Have a left ventricular ejection fraction (LVEF) ≥50% by echocardiography (ECHO) within 28 days prior to first study drug administration.

10. Have recovered from all toxicities due to prior therapy (i.e., improved to Grade 0 or 1, or to levels specified in the eligibility criteria). Participants with unresolved, stable chronic (>3 months) toxicities not considered a safety risk (e.g., alopecia, hyperpigmentation, vitiligo) may be enrolled.

    Gender and Contraceptive Requirements

11. Participants must agree to use highly effective contraception during study treatment.

Note: The reliability of abstinence as required in the eligibility criteria must be evaluated based on the duration of the clinical study and the participant's preferred and usual lifestyle. Periodic abstinence (e.g., calendar method, ovulation method, symptothermal method, or post-ovulation method) is not an acceptable contraceptive method.

Female participants eligible for study participation must be non-pregnant (see Appendix 3), non-lactating, and meet at least one of the following conditions:

• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3. OR
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 from the time of informed consent signing through at least 6 months after the last dose of study treatment.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded:

Prior/Current Study Experience

1. Participation in any other interventional clinical study, except for observational (non-interventional) studies or follow-up periods of interventional studies.

   Disease Characteristics

2. For participants with ovarian cancer, mixed tumors containing sarcomatous components or borderline ovarian tumors.

   - For participants in Cohorts C-E, mixed tumors containing high-grade serous carcinoma components and other components, or endometrioid, clear cell, mucinous, or sarcomatous histology, or mixed tumors containing any of the above histological types, or low-grade/borderline ovarian tumors.

   Prior/Concomitant Therapy

3. Prior receipt of any of the following treatments:

   a) Any drug therapy targeting topoisomerase I, including irinotecan, topotecan hydrochloride for injection, antibody-drug conjugates (ADCs) containing topoisomerase I, etc.

4. Receipt of other antineoplastic therapy within 4 weeks prior to first study drug administration, including systemic chemotherapy, targeted therapy, immunotherapy, intraperitoneal perfusion chemotherapy, tumor embolization, or interventional chemotherapy, etc. For oral PARP inhibitors and traditional Chinese medicines indicated for antineoplastic therapy, the washout period is 2 weeks or 5 half-lives, whichever is longer.

5. Receipt of strong cytochrome P450 (CYP3A4) inhibitors or inducers, or BCRP inhibitors (see Appendix 8) within 2 weeks prior to first dose or within 5 half-lives of the known drug, whichever is longer.

6. Receipt of live vaccine vaccination within 4 weeks prior to first study drug administration, or planned receipt of any live vaccine during the study.

7. Persistence of adverse reactions from prior antineoplastic therapy that have not resolved to Grade 0, Grade 1, or baseline status per NCI-CTCAE v5.0 criteria prior to first study drug administration. Participants with unresolved, stable chronic (>3 months) toxicities not considered a safety risk (e.g., alopecia, hyperpigmentation, vitiligo) may be enrolled.

8. Major surgery (craniotomy, thoracotomy, or laparotomy, and other surgical types considered "major" by the investigator, excluding needle biopsy) within 4 weeks prior to first study drug administration, or anticipated major surgery during the study, or presence of serious unhealed wounds, trauma, or ulcers, etc.

   Note: Palliative local surgical treatment for isolated lesions is acceptable.

9. Palliative radiotherapy within 2 weeks prior to first drug administration, or definitive radiotherapy within 4 weeks prior to first drug administration.

10. Any condition requiring systemic corticosteroid therapy (dose >10 mg/day prednisolone or equivalent) or other immunosuppressive therapy within 14 days prior to first study drug administration. Participants receiving intranasal, inhaled, topical, or local glucocorticoid injections (e.g., intra-articular injections), or glucocorticoids as prophylaxis for hypersensitivity reactions may be enrolled.

    Medical Conditions

11. Known symptomatic central nervous system (CNS) metastasis and/or spinal cord compression and/or carcinomatous meningitis, or history of leptomeningeal carcinomatosis. Participants with asymptomatic CNS metastases (no neurological symptoms, no corticosteroid treatment required, and all metastatic lesions ≤1.5 cm in diameter) or with brain metastases that have been treated and are stable may be considered for enrollment if all of the following criteria are met: (a) Measurable disease outside the CNS; (b) No midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord metastases; (c) Stable condition for at least 4 weeks with no new or enlarging metastases (clearly documented by clinical evidence); (d) Discontinuation of corticosteroids or anticonvulsants at least 2 weeks prior to first study drug administration. CNS lesions should be monitored regularly during the study.

12. History of corticosteroid-treated pneumonitis, or history of other clinically significant pulmonary disease (e.g., interstitial lung disease, non-infectious pneumonia, or uncontrolled pulmonary disease such as pulmonary fibrosis, severe radiation pneumonitis, and acute lung injury), or participants with suspected such disease on imaging during screening; clinically significant pulmonary function impairment due to concurrent pulmonary disease, including but not limited to: any serious underlying pulmonary disease (e.g., severe asthma, severe chronic obstructive pulmonary disease, or restrictive lung disease), or any autoimmune disease, connective tissue disease, or inflammatory disease potentially involving the lungs (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.).

13. Presence of the following conditions:

    1. Infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first study drug administration; serious infection within 4 weeks prior to first study drug administration, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia;
    2. Human immunodeficiency virus (HIV) infection, or HIV-positive (HIV 1/2 Ab positive);
    3. Acute or chronic active hepatitis B, defined as positive hepatitis B surface antigen (other antigen/antibody results unrestricted) or positive hepatitis B core antibody only (negative hepatitis B surface antibody and negative hepatitis B e antibody), with HBV DNA copy number ≥1×10⁴ copies/mL or ≥2000 IU/mL; acute or chronic active hepatitis C, defined as positive hepatitis C virus (HCV) antibody with HCV RNA titer above the lower limit of detection;
    4. Symptomatic coronavirus disease 2019 (COVID-19) infection requiring treatment or resulting in hospitalization, such as fever, dyspnea, nausea, vomiting, diarrhea, etc.;
    5. Active tuberculosis infection, or currently receiving anti-tuberculosis treatment, or received anti-tuberculosis treatment within 1 year prior to first study drug administration;
    6. Active syphilis infection or latent syphilis requiring treatment;
    7. Uncontrolled myocarditis, or symptomatic congestive heart failure Grade II-IV (New York Heart Association [NYHA] criteria), symptomatic or uncontrolled arrhythmias such as ventricular tachycardia, atrial fibrillation, ventricular fibrillation, torsades de pointes, etc., QTc interval >480 ms, personal or family history of congenital long/short QT syndrome;
    8. Uncontrolled hypertension despite standardized treatment or uncontrolled despite standardized treatment (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg);
    9. Gastrointestinal tract [referring to the muscular tube from mouth to anal canal, including oral cavity, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, appendix, colon, rectum), and anal canal] or tracheal lumen stent implantation;
    10. Significant malnutrition, such as requiring intravenous nutritional supplementation due to malnutrition; except if malnutrition was corrected >4 weeks prior to first study treatment.
    11. History of deep vein thrombosis, pulmonary embolism, or any other serious thromboembolism within 3 months prior to first study drug administration (thrombosis due to implanted venous access ports or catheter-related thrombosis, or superficial venous thrombosis are not considered serious thromboembolism).
    12. History of any arterial thromboembolic event within 6 months prior to first study drug administration, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
    13. Bleeding within 3 months prior to first study drug administration that was life-threatening, required transfusion, or required invasive treatment.
    14. Symptomatic pelvic/abdominal effusion (excluding pelvic/abdominal effusion due to ovarian cancer itself), pleural effusion, or pericardial effusion requiring intervention (participants with stable, controlled effusion are permitted, defined as no significant increase in effusion volume and no clinical symptoms for at least 7 days with drainage tube removed or without drainage).
    15. Participants with biliary obstruction unless local treatment for the obstruction has been performed (e.g., endoscopic stent placement or percutaneous transhepatic drainage) and TBIL has decreased to below 1.5×ULN.
    16. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh Class B or higher cirrhosis.
    17. History of prior gastrointestinal perforation or fistula formation, unhealed gastrointestinal obstruction, or participants at risk of gastrointestinal obstruction or perforation (including but not limited to acute diverticulitis, abdominal abscess, history of abdominal cancer), participants with recurrent gastrointestinal obstruction (defined as ≥2 episodes of gastrointestinal obstruction within one year, or prior gastrointestinal obstruction in 2 consecutive years), or history of the following conditions: extensive bowel resection (partial colectomy or extensive small bowel resection with concurrent chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
    18. Clinically significant proteinuria.
    19. History of severe dry eye, meibomian gland disease (MGD) and/or blepharitis, keratoconjunctivitis sicca (KSC), corneal disorders causing non-healing or delayed healing of the cornea, or macular disorders. Or determination of keratoconjunctivitis and/or corneal ulcer on ophthalmologic examination during screening, and presence of active or chronic corneal disease, other active eye disease requiring continuous treatment, or any clinically significant corneal disease preventing adequate monitoring of drug-induced keratopathy.

14. Known hypersensitivity to study drug or any of its components [including polysorbate 80 (II)], or history of serious allergic reaction to other monoclonal antibodies; known history of platinum hypersensitivity for Cohort C; known history of platinum or bevacizumab hypersensitivity for Cohort D; known history of bevacizumab hypersensitivity for Cohort E; and hypersensitivity to both CT and MRI contrast agents, or inability to undergo contrast-enhanced CT and contrast-enhanced MRI for any reason.

15. History of immunodeficiency disorders, including congenital or acquired immunodeficiency diseases.

16. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

17. Pregnant or lactating women.

    Tumor History

18. Participants with known other malignancies progressing within the past 5 years or requiring active treatment. Exceptions include adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical carcinoma in situ with no evidence of disease recurrence.

19. Tumor invasion of surrounding vital organs or tissues (e.g., mediastinal great vessels, superior and inferior vena cava, pericardium, heart, trachea, esophagus, etc.) and/or risk of gastrointestinal, respiratory, or other fistulas due to any cause.

    Other Exclusion Criteria

20. Presence of other acute or chronic diseases or laboratory abnormalities that may increase the risk of study participation or administration, or interfere with interpretation of study results; presence of neurological, psychiatric, or social conditions affecting trial compliance, significantly increasing the risk of adverse events, or affecting the participant's ability to provide written informed consent.

21. Acute or chronic diseases or laboratory abnormalities that the investigator judges unsuitable for study participation, or any condition that the investigator believes interferes with evaluation of study drug, participant safety, or interpretation of study results, or any other condition that the investigator believes makes the participant unsuitable for this study.