This is a single-center, prospective, open-label, single-arm, phase Ib/II study evaluating the safety and efficacy of neoadjuvant propranolol combined with SOX chemotherapy and toripalimab in patients with resectable locally advanced gastric or gastroesophageal junction adenocarcinoma. A total of 49 participants will be enrolled. Stage 1 includes an initial safety lead-in of 12 participants, followed by efficacy evaluation using a Simon two-stage design. Participants will receive propranolol, toripalimab, oxaliplatin, and S-1 during the neoadjuvant period, followed by curative-intent surgery.
The primary efficacy endpoint is pathological complete response. Secondary endpoints include safety and tolerability, major pathological response, R0 resection rate, event-free survival, recurrence-free survival, and overall survival. Exploratory analyses will assess changes in adrenergic stress markers, heart rate variability, peripheral immune parameters, β-adrenergic receptor signaling, and the tumor immune microenvironment.
Inclusion Criteria:
(1)No clinically significant abnormality on electrocardiography; (2)Resting heart rate of at least 60 beats per minute; (3)Systolic blood pressure of at least 90 mmHg; (4)No progressive or decompensated cardiopulmonary disease; (5)Left ventricular ejection fraction of at least 50%. 6.Adequate organ function during screening, defined as follows:
7.Female participants of childbearing potential must have a negative pregnancy test during screening. Male and female participants of reproductive potential must agree to use effective contraception during the study and for at least 6 months after the last dose of study treatment.
Exclusion Criteria:
(1)Bronchial asthma or a risk of bronchospasm; (2)Diabetic ketoacidosis or metabolic acidosis; (3)Severe or symptomatic bradycardia; (4)Second- or third-degree atrioventricular block, sinoatrial block, or sick sinus syndrome; (5)Cardiogenic shock; (6)Right-sided heart failure caused by pulmonary hypertension; (7)Congestive heart failure; (8)Clinically significant hypotension; (9)Prolonged fasting; (10)Severe peripheral circulatory failure; (11)Untreated pheochromocytoma; (12)Variant angina; (13)Concomitant treatment with rizatriptan benzoate. 10.Moderate or severe chronic obstructive pulmonary disease with a recent acute exacerbation.
11.Active upper gastrointestinal bleeding at baseline, melena or hematemesis within the previous 4 weeks, bleeding requiring blood transfusion or endoscopic hemostasis, uncontrolled peptic ulcer disease, or a high risk of recent bleeding as determined by the investigator.
12.Requirement for continuous full-dose anticoagulation, dual antiplatelet therapy that cannot be interrupted, or a bleeding disorder that cannot be adequately managed during the perioperative period.
13.Known hypersensitivity to propranolol, oxaliplatin, S-1 or fluoropyrimidines, toripalimab, or any of their excipients, or a history of a severe adverse reaction to any of these agents.
14.Concomitant use of medications that cannot be discontinued or replaced and that may cause clinically significant interactions with propranolol, including verapamil, diltiazem, class I or class III antiarrhythmic agents, strong CYP2D6 or CYP1A2 inhibitors, or other medications considered by the investigator to pose a major drug-drug interaction risk.
15.Uncontrolled bleeding disorder, or major surgery or serious trauma within 4 weeks before enrollment, excluding the curative-intent surgery planned as part of this study.
16.Pregnancy or breastfeeding, or unwillingness to use the required contraceptive measures.
17.Any medical, psychiatric, social, or other condition that, in the investigator's judgment, may compromise participant safety, treatment compliance, or completion of the required follow-up, including severe psychiatric illness, substance abuse, or inability to attend scheduled visits.
liqing@scu.edu.cn+8618702848178
Pathological outcomes will be independently assessed by two gastrointestinal pathologists blinded to relevant treatment information. Disagreements will be resolved by a third pathologist.
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