Oral Paclitaxel Plus Fruquintinib Verus Investigator's Choice in Second-Line Advanced Gastric Cancer

Paclitaxel Oral Solution Plus Fruquintinib Versus Investigator's Choice as Second-Line Treatment for Advanced Gastric Cancer: A Multicenter, Open-Label, Randomized Controlled Trial

The goal of this study is to evaluate the efficacy and safety of oral paclitaxel solution plus fruquintinib as second-line therapy in adult subjects with advanced or metastatic gastric (G) or gastroesophageal junction (GEJ) cancer.

Inclusion Criteria:

1. Age 18 to 75 years, regardless of sex;

2. Histologically and/or cytologically confirmed advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma that has failed first-line therapy or developed intolerable toxicity to first-line treatment.

3. Presence of at least one measurable lesion per RECIST v1.1 criteria (Note: Previously irradiated lesions cannot be used as target lesions unless unequivocal progression of the lesion after radiotherapy is documented);

4. Body weight ≥40 kg or BMI >18.5 kg/m²;

5. No severe hematologic, hepatic, or renal abnormalities:

   1. Hematology: Absolute neutrophil count (ANC) ≥1.5×10⁹/L; Platelet count (PLT) ≥100×10⁹/L; Hemoglobin (Hb) ≥90 g/L;
   2. Chemistry: Total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); ALT and AST ≤2.5×ULN in the absence of liver metastases, or ≤5×ULN if liver metastases are present; Serum creatinine (Cr) ≤1.5×ULN;
   3. Urinalysis: Urine protein ≤1+; If urine protein is ≥2+, a 24-hour urine protein test must be performed, and enrollment is permitted only if the 24-hour urine protein is <1.0 g;

6. ECOG Performance Status (PS) 0-1;

7. Life expectancy ≥12 weeks;

8. Signed informed consent.

Exclusion Criteria:

1. Known HER2-positive status without prior anti-HER2 therapy (patients who progressed after anti-HER2 therapy are eligible);
2. History of another primary malignancy within 3 years prior to the first study drug administration, except for adequately treated basal cell or squamous cell carcinoma of the skin, or in situ carcinomas of the cervix, breast, or other sites;
3. Receipt of radiotherapy (except palliative radiotherapy), chemotherapy, or small-molecule targeted anticancer therapy within 4 weeks or within 5 half-lives of the agent (whichever is shorter) prior to the first dose of study drug. Patients who discontinued other investigational agents for more than 5 half-lives are eligible for screening. Additionally, treatment with large-molecule targeted anticancer agents within 4 weeks prior to the first study drug dose is prohibited;
4. Toxicity from prior anticancer therapy not recovered to ≤ Grade 1 or baseline levels (except alopecia; neurotoxicity must have resolved to ≤ Grade 2) within 2 weeks prior to the first study drug administration;
5. Presence of dysphagia, uncontrolled nausea, vomiting, diarrhea, or known malabsorption syndrome that may interfere with oral drug absorption;
6. Active gastrointestinal conditions such as gastric/duodenal ulcer, ulcerative colitis, or bowel obstruction, or any other condition deemed by the investigator to carry a risk of gastrointestinal hemorrhage or perforation; history of gastrointestinal perforation or fistula within the past 6 months; or incomplete recovery from surgery related to gastrointestinal perforation or fistula;
7. Evidence of significant bleeding or history of bleeding (e.g., hematemesis, hemoptysis) within 2 months prior to randomization. Patients with melena and positive fecal occult blood test must undergo gastroenteroscopy to rule out active bleeding or active ulcer before enrollment;
8. Requirement for long-term use of proton pump inhibitors (PPIs) or H2-receptor antagonists during the trial; or use of strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 or CYP2C8 within 2 weeks prior to the first study drug dose;
9. Known active central nervous system (CNS) metastases and/or leptomeningeal carcinomatosis;
10. Active infections or serious infectious diseases, including but not limited to: HIV infection (positive HIV antibody), active hepatitis (active HCV infection defined as positive HCV RNA; HCV antibody-positive but RNA-negative patients are allowed), active HBV infection (HBsAg-positive with HBV DNA >2000 IU/mL), bacteremia, severe pneumonia requiring systemic therapy, or active tuberculosis;
11. Any of the following cardiovascular conditions: myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Class ≥2), or other clinically significant cardiac disease within 6 months prior to the first study drug dose; clinically significant ECG abnormalities (e.g., arrhythmias, QTc interval >450 ms); left ventricular ejection fraction (LVEF) <50% on echocardiography; or uncontrolled hypertension despite treatment with ≥2 antihypertensive agents (systolic BP >140 mmHg or diastolic BP >90 mmHg);
12. Prior systemic therapy targeting VEGF or VEGFR; or prior treatment with paclitaxel, docetaxel, nab-paclitaxel, liposomal paclitaxel, or polymeric micelle paclitaxel;
13. Known hypersensitivity to any component of the investigational product;
14. Pregnant or lactating women;
15. Uncontrolled symptomatic pleural, peritoneal, or pericardial effusion requiring repeated drainage. Asymptomatic patients with minimal effusions detected only on imaging and who have not received drainage or other intervention within 2 weeks prior to enrollment are eligible;
16. Major surgery (e.g., craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to first dosing, or presence of non-healed surgical wounds, ulcers, or fractures. Patients may be enrolled if the investigator determines they are fit to receive study drug ≥2 weeks post-surgery;
17. History of deep vein thrombosis, pulmonary embolism, or other significant thromboembolic events within 3 months prior to study entry; ongoing anticoagulation therapy with warfarin, low-molecular-weight heparin, or similar agents. Prophylactic low-dose anticoagulation is permitted if INR ≤1.5 per inclusion criteria;
18. Chronic use of nonsteroidal anti-inflammatory drugs (e.g., indomethacin, ibuprofen) or antiplatelet agents (e.g., clopidogrel, ticlopidine, dipyridamole). Low-dose aspirin (≤325 mg/day) is allowed;
19. Any other condition deemed by the investigator as unsuitable for participation in this study.