Neoadjuvant Propranolol Plus SOX and Toripalimab for Locally Advanced Gastric/GEJ Adenocarcinoma

ConditionsGastric or Gastroesophageal Junction Adenocarcinoma Propranolol SOX Chemotherapy Toripalimab

Trial statusNot yet recruiting

Trial phasePhase 1, Phase 2

Trial typeInterventional

Biological sexAll

Age18-75

SponsorTing Liu

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Voluntary participation in the study, with written informed consent, and willingness and ability to comply with the study treatment and follow-up requirements.

Male or female participants aged 18 to 75 years.

Histologically or cytologically confirmed gastric or gastroesophageal junction adenocarcinoma.Resectable locally advanced disease as determined by imaging assessment or a multidisciplinary team according to the eighth edition of the American Joint Committee on Cancer staging system, generally defined as cT3-4a with any N category, or any T category with node-positive disease, corresponding to stage II-III disease, without distant metastasis.

Eastern Cooperative Oncology Group performance status of 0 or 1.

Disqualifiers

Distant metastatic disease confirmed by imaging or diagnostic laparoscopy, including but not limited to peritoneal, hepatic, or bone metastases, or positive peritoneal cytology.

Previous systemic anticancer treatment for the current malignancy, including chemotherapy, immunotherapy, or targeted therapy, or previous radiotherapy. Diagnostic endoscopy and biopsy are permitted.

Grade 2 or higher peripheral neuropathy at baseline.

A second primary malignancy requiring systemic treatment within the previous 3 years, except for adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, low-risk thyroid cancer, or other malignancies considered cured.

Trial design

Design model

Single group

Treatments tested in this trial

propranolol
Drug
Propranolol will be administered orally at 10 mg twice daily beginning on Day 1 of the first neoadjuvant treatment cycle. The dose may be reduced to 5 mg twice daily, temporarily interrupted, or discontinued according to tolerability and predefined safety criteria, including heart rate, blood pressure, respiratory symptoms, and cardiac conduction abnormalities. Propranolol may be continued during postoperative treatment until completion of adjuvant therapy or the occurrence of unacceptable toxicity.
Toripalimab
Drug
Toripalimab will be administered intravenously at a fixed dose of 240 mg on Day 1 of each 21-day cycle. Participants will receive 3 neoadjuvant cycles before surgery. After surgery, 3 additional cycles are recommended, followed by toripalimab maintenance as clinically appropriate for a total immunotherapy duration of up to 1 year from the first dose.
Oxaliplatin
Drug
Oxaliplatin will be administered intravenously at 130 mg/m² on Day 1 of each 21-day cycle. Participants will receive 3 neoadjuvant cycles before surgery. Three additional postoperative cycles are recommended according to postoperative recovery, tolerability, and the investigator's assessment. Dose modification, interruption, or discontinuation will be permitted for treatment-related toxicity.
S-1
Drug
S-1 will be administered orally twice daily on Days 1-14 of each 21-day cycle, followed by a 7-day rest period. The total daily dose will be determined according to body surface area: 80 mg/day for body surface area below 1.25 m², 100 mg/day for body surface area of 1.25-1.49 m², and 120 mg/day for body surface area of 1.50 m² or greater. Participants will receive 3 neoadjuvant cycles, with 3 additional postoperative cycles recommended according to tolerability and postoperative recovery.

Treatment groups

49 Participants

are divided into 1 treatment group

Group A: Propranolol Plus SOX and ToripalimabExperimental treatment 4 interventions

Trial outcomes

Primary outcomes

Pathological Complete Response (pCR) Rate

The proportion of participants with no residual viable tumor cells in the resected primary tumor and all dissected regional lymph nodes following neoadjuvant treatment, corresponding to Becker grade 1a. Participants who do not undergo surgery or do not have an assessable pathological result will be classified as non-pCR in the intention-to-treat analysis.

Time frame

At curative-intent surgery following completion of 3 neoadjuvant treatment cycles, approximately 13 to 15 weeks after treatment initiation.

Secondary outcomes

Dose-Limiting Toxicity (DLT) Rate During the Safety Lead-in

The proportion of participants in the initial safety lead-in cohort who experience a dose-limiting toxicity related to study treatment. DLTs include predefined severe hematologic, nonhematologic, immune-related, cardiovascular, respiratory, or gastrointestinal toxicities; treatment-related death; or treatment-related toxicity resulting in a treatment delay of more than 21 days or inability to undergo planned surgery.

Time frame

From the first dose of study treatment through 30 days after surgery

Incidence of Treatment-Related Adverse Events

The proportion of participants who experience treatment-related adverse events, serious adverse events, or immune-related adverse events. Adverse events will be graded according to the Common Terminology Criteria for Adverse Events, version 5.0.

Time frame

From the first dose of study treatment through at least 30 days after the last dose, or until treatment-related adverse events have resolved or stabilized

Postoperative Complication Rate

The proportion of participants who experience postoperative complications following curative-intent surgery. Complications will be classified according to the Clavien-Dindo classification.

Time frame

Within 30 days after surgery

Major Pathological Response (MPR) Rate

The proportion of participants with 10% or less residual viable tumor cells in the resected primary tumor following neoadjuvant treatment. Participants who do not undergo surgery or do not have an assessable pathological result will be classified as non-MPR in the intention-to-treat analysis.

Time frame

At curative-intent surgery following completion of neoadjuvant treatment, approximately 13 to 15 weeks after treatment initiation

Other outcomes

Tumor Beta-Adrenergic Receptor Expression and Localization

Beta-adrenergic receptor expression and cellular localization in resected tumor tissue will be evaluated using immunohistochemical and spatial analyses. Associations with pathological response and tumor immune microenvironment features will be explored.

Time frame

At curative-intent surgery following completion of neoadjuvant treatment, approximately 13 to 15 weeks after treatment initiation

Tumor Immune Microenvironment Features

The density, phenotype, and spatial distribution of immune cells in resected tumor tissue will be evaluated using multiplex immunohistochemistry and digital pathology. Exploratory markers may include CD8-positive T cells, regulatory T cells, myeloid-derived suppressor cells, and CD68-positive or CD163-positive macrophages.

Time frame

At curative-intent surgery following completion of neoadjuvant treatment, approximately 13 to 15 weeks after treatment initiation

Locations

This trial has no locations.

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Ting Liu

Lead sponsor

West China Second University Hospital

Sponsor institution

Source ClinicalTrials.gov

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