Sac-TMT Combined With Fruquintinib as Second-Line Treatment in Patients With Advanced Gastric/Gastroesophageal Junction Adenocarcinoma (SKB264-Fru-GA)

Inclusion Criteria:

• Histologically and/or cytologically confirmed metastatic or locally advanced adenocarcinoma of the gastric or gastroesophageal junction, unresectable;
• Subjects who have failed first-line standard systemic therapy, or experienced disease progression or recurrence within 6 months after completion of adjuvant systemic therapy (HER2-positive subjects must have received prior anti-HER2 therapy);
• Have at least one measurable lesion per RECIST v1.1, subjects with only cutaneous or bone lesions are not eligible for enrollment;
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 within 7 days prior to study drug administration;
• Estimated life expectancy > 12 weeks.

• Adequate organ and bone marrow function (no transfusions, recombinant human thrombopoietin or colony-stimulating factor administered within 2 weeks prior to dosing), defined as follows:

  1. Hematology: Absolute neutrophil count (NEUT#) ≥ 1.5×10⁹/L; platelets (PLT) ≥ 80×10⁹/L; hemoglobin ≥ 90 g/L;
  2. Hepatic function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN); for subjects with baseline liver metastases, ALT and AST ≤ 5 × ULN; albumin ≥ 30 g/L; total bilirubin (TBIL) ≤ 1.5 × ULN;
  3. Renal function: Creatinine clearance ≥ 50 mL/min (calculated using the standard Cockcroft-Gault formula);
  4. Coagulation function: International normalized ratio (INR), activated partial thromboplastin time (APTT) and prothrombin time (PT) ≤ 1.5 × ULN.
• All acute toxicities from prior treatments have recovered to Grade 1 or lower (alopecia and vitiligo are excluded). Note: Subjects with any grade of prior endocrine adverse events may be enrolled if they only require maintenance hormone replacement therapy and are stable and asymptomatic at screening.
• Females of childbearing potential and males with partners of childbearing potential must agree to use effective medical contraception from the time of informed consent signature through 6 months after the last dose of study drug;
• The subject voluntarily participates in this study, signs the informed consent form, and is able to comply with protocol-specified study visits and related procedures.

Exclusion Criteria:

• Participants unable to receive oral administration due to dysphagia, intractable vomiting, or known drug malabsorption;
• Participants with active gastric/duodenal ulcer, ulcerative colitis, intestinal obstruction, or other gastrointestinal disorders/conditions judged by the Investigator to carry a risk of gastrointestinal hemorrhage or perforation; or with a history of intestinal perforation or fistula within the preceding 6 months; or with unresolved intestinal perforation/fistula following prior surgical repair;
• Participants with known meningeal metastasis, brainstem metastasis, spinal cord metastasis and/or spinal cord compression, or active/untreated central nervous system (CNS) metastases. Participants with previously locally treated brain metastases may be enrolled if clinically stable for at least 4 weeks prior to dosing and not requiring corticosteroids or anticonvulsants for a minimum of 14 days before the first dose;
• Participants diagnosed with another malignant tumor within 3 years prior to dosing, except malignancies cured by local therapy such as basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, carcinoma in situ of the cervix, etc.;

• Participants with clinically significant cardiovascular disease, defined as:

  1. Severe or uncontrolled cardiac disease or symptomatic cardiac conditions requiring treatment within 6 months prior to the first study dose, including congestive heart failure classified as New York Heart Association (NYHA) Class III or IV, medically refractory unstable angina, severe arrhythmias requiring pharmacotherapy (excluding atrial fibrillation or paroxysmal supraventricular tachycardia), and myocardial infarction;
  2. Prior history of myocarditis or cardiomyopathy;
  3. Baseline corrected QT (QTc) interval > 480 ms;
• Participants with a history of arterial thromboembolism or deep vein thrombosis within the preceding 6 months;
• Participants with documented or historical significant bleeding within 2 months prior to dosing, including melena, hematemesis, hemoptysis, ≥++ fecal occult blood. Subjects with 1+ fecal occult blood and underlying primary gastrointestinal lesions must complete gastroscopy prior to enrollment to rule out active bleeding or ulcers;
• Participants with a history of stroke and/or transient ischemic attack (TIA) within 12 months prior to dosing;
• Participants with severe and/or uncontrolled systemic diseases, such as unregulated metabolic disorders, active inflammatory bowel disease, or gastrointestinal perforation;
• Participants with active hepatitis B [hepatitis B surface antigen (HBsAg)-positive, with HBV-DNA ≥1000 IU/mL or above the lower limit of quantification (LLOQ), whichever is higher] or hepatitis C (hepatitis C antibody-positive with HCV-RNA above the LLOQ). Note: HBsAg-positive subjects must receive anti-HBV antiviral therapy throughout study treatment;
• Participants with known poorly controlled human immunodeficiency virus (HIV) infection; subjects with active syphilis infection;
• Participants with known active pulmonary tuberculosis;
• Participants who have undergone major surgery (as defined by the Investigator) within 30 days prior to the first study dose, or are still in the postoperative recovery phase from prior surgery;
• Participants with a history of severe hypersensitivity reactions to the study drug (including its excipients);
• Participants with a history of non-infectious interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroid therapy; current ILD or non-infectious pneumonitis; or suspected ILD/non-infectious pneumonitis that cannot be ruled out via imaging at screening;
• Participants with a history of allogeneic tissue/organ transplantation;

• Participants previously treated with any of the following regimens (including adjuvant or neoadjuvant settings):

  1. TROP2-targeted therapy;
  2. Any therapy containing topoisomerase I inhibitors, including antibody-drug conjugates (ADCs);
  3. Systemic therapy targeting the vascular endothelial growth factor receptor (VEGFR) signaling pathway;
• Participants who received live vaccines within 30 days prior to dosing, or plan to receive live vaccines during the study period;
• Participants requiring strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 2 weeks before the first dose and throughout the study;
• Participants who received chemotherapy, radiotherapy, immunotherapy, or biotherapy within 4 weeks before the first study dose;
• Participants who received small-molecule tyrosine kinase inhibitors (TKIs), anti-tumor hormonal therapy, systemic immune stimulants (including but not limited to interferon, IL-2), or proprietary Chinese medicines with approved anti-tumor indications within 2 weeks before the first study dose;
• Participants with active infection requiring systemic anti-infective therapy within 2 weeks prior to dosing;
• Participants with any disease requiring systemic corticosteroids (>10 mg prednisone equivalent daily) or other immunosuppressants within 14 days before the first study drug administration. Nasal, inhaled, topical, intra-articular corticosteroids, and corticosteroids administered for prophylaxis of infusion reactions are permitted;
• Participants with documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or corneal disorders with a history of impaired/delayed corneal wound healing;
• Pregnant or breastfeeding women, or women of childbearing potential with a positive pregnancy test prior to the first dose;
• Participants with urine protein ≥2+ and 24-hour urinary protein >1 g; or with uncontrolled hypertension despite antihypertensive medication (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg);
• Any other condition that, in the Investigator's judgment, renders the subject unsuitable for participation in this study.