Neoadjuvant of Sintilimab Combined Weekly Metronomic Chemotherapy (PLOF) for Resectable Locally Advanced Gastric Cancer

Study Overview
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Brief Summary
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To evaluate efficacy and safety of Neoadjuvant of Sintilimab Combined Weekly Metronomic Chemotherapy (PLOF) in resectable locally advanced gastric cancer.

Detailed Description
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This is a single-arm clinical study to enroll 50 patients with gastric cancer (cTNM diagnosis of cT3-4aN1-3M0). Each enrolled patient will be assigned a case number. Both this case number and the patient's initials will be entered on each page of the case report form. Enrolled patients receive a neoadjuvant regimen of POLF in combination with sindilizumab: preoperatively, they receive a POLF regimen (paclitaxel 60 mg/m2, oxaliplatin 50 mg/m2, and 5-fluorouracil 425 mg/m2) administered once weekly for a total of 6 doses, and in combination with sindilizumab 200 mg intravenously once every 3 weeks for a total of 2 doses. Upon completion of the evaluation, patients whose tumors were judged to be resectable underwent radical surgery and received six postoperative doses of the POLF regimen and two doses of Sindilizumab as adjuvant therapy. Postoperative imaging evaluations will be performed every three months until disease recurrence. Survival follow-up was performed every three months after disease recurrence. Patients will receive neoadjuvant therapy for 6 weeks preoperatively and adjuvant therapy for 6 weeks postoperatively unless intolerable toxicity occurs, the patient refuses to continue treatment, or treatment is delayed beyond 3 weeks. Patients will be under study observation during treatment and 30 days after treatment termination, and will receive long-term follow-up for 5 years postoperatively. Ultimately, pCR and MPR will be the primary study endpoints, and ORR, DCR, 2-year PFS rate, 3-year OS rate and safety will be the secondary study endpoints to evaluate the efficacy and safety of the neoadjuvant regimen of POLF combined with sindilizumab, as well as to explore the immune activation effect and mechanism of the regimen using peripheral blood and tumor tissue samples.

Official Title
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Neoadjuvant of Sintilimab Combined Weekly Metronomic Chemotherapy (PLOF) for Resectable Locally Advanced Gastric Cancer : A Phase Il Study

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: sintilimab+metronomic PLOF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written Informed Consent Form Male or female, age ≥ 18 years old Histologically confirmed gastric adenocarcinoma, diagnosed as locally progressive according to the AJCC 8th ed, cTNM diagnosis of cT3-4aN1-3M0 and resectable lesion as assessed by the investigator No prior systemic therapy such as surgery, radiotherapy, or immunotherapy for the disease at hand Consent to radical surgical treatment and no contraindications to surgery as determined by the surgeon ECOG PS: 0-1 score Expected survival > 6 months Adequate organ function, must meet the following laboratory specifications: 8.1 Absolute neutrophil count (ANC) ≥ 1.0x10^9/L; 8.2 Platelets ≥ 80x10^9/L; 8.3 Hemoglobin > 7g/dL; 8.4 Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Total bilirubin > 1.5 x ULN but direct bilirubin ≤ ULN are allowed to be enrolled); 8.5 AST, ALT ≤ 2.5×ULN; 8.6 Blood creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min; 8.7 INR or PT ≤ 1.5 times ULN; 8.8 TSH within normal range (Enrollment allowed if baseline TSH is outside normal range but FT4 is within normal range); 8.9 Myocardial enzyme profile within normal range; Negative pregnancy test in women of childbearing age Need to use contraception with an annual failure rate of less than 1% if there is a risk of conception Exclusion Criteria: Endoscopically show signs of active bleeding from the lesion Current participation in an interventional clinical study or treatment with another investigational drug or use of an investigational device within 4 weeks prior to the first dose of study drug Prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or agents targeting CTLA-4, OX-40, CD137, etc. Diagnosis of a malignant disease other than gastric cancer within 5 years prior to the first dose of therapy Active autoimmune disease requiring systemic therapy within 2 years prior to the first dose of the drug Live vaccination within 30 days prior to the first administration of the drug Have received systemic systemic therapy with proprietary Chinese medicines with antitumor indications or immunomodulatory drugs within 2 weeks prior to the first administration of the drug Have received systemic glucocorticoid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment Has not fully recovered from any intervention-induced toxicity and/or complications (excluding malaise or alopecia) prior to initiation of therapy Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation Known hypersensitivity to drugs used in this study Known history of HIV infection Untreated active hepatitis B Active HCV infection Pregnant or lactating women The presence of any serious or uncontrolled systemic disease Other factors that, in the judgment of the investigator, may affect the outcome of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sintilimab+metronomic PLOF<br>sintilimab therapy(200mg, iv,d1,Q3W, 2cycles)and PLOF chemotherapy (Paclitaxel 60 mg/m2, oxaliplatin 50 mg/m2, 5-fluorouracil 425mg/m2, d1, QW, 6cycles) followed by adjuvant sintilimab therapy(200mg, iv,d1,Q3W, 2cycles)and PLOF chemotherapy (Paclitaxel 60 mg/m2, oxaliplatin 50 mg/m2, 5-fluorouracil 425mg/m2, d1, QW, 6cycles) neoadjuvant chemotherapy (8 weeks) preceding surgery (3 weeks after completion of chemotherapy) followed by adjuvant chemotherapy (16 weeks, begin within 12 weeks after surgery) | Drug: sintilimab+metronomic PLOF<br>* Drug: Sintilimab 200mg iv d1 Q3W, 2cycles Drug: Paclitaxel 60 mg/m2, d1, QW,6cycles Drug: Oxaliplatin 50 mg/m2, d1, QW, 6cycles Drug: 5-fluorouracil 425mg/m2 ,d1 ,QW, 6cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with no residual surviving tumor cells in resection specimens and lymph nodes | Pathological complete response rate (pCR), defined as the proportion of participants with no residual viable tumor cells on microscopy and negative lymph nodes as a percentage of all participants. We will evaluate pathological complete response rate of primary tumor and locally metastatic lymph nodes after 6 weeks of neoadjuvant therapy. | up to 6 weeks after first dosing | 
| Percentage of participants with ≤10% tumor cell survival in resection specimens | Major pathologic response (MPR) rate, defined as the proportion of participants with ≤10% surviving tumor cells in the resection specimen as a percentage of all participants. We will evaluate major pathological response rate of primary tumor and locally metastatic lymph nodes after 6 weeks of neoadjuvant therapy. | up to 6 weeks after first dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants achieving complete remission (CR) and partial remission (PR) after treatment | Objective remission rate (ORR), the percentage of participants whose tumors shrink by a certain amount and remain there for a certain period of time, including complete remission (CR) and partial remission (PR). CR (Complete remission): Complete disappearance of the target lesion, with no new lesions produced, and lasting for more than 4 weeks. PR (Partial remission): the sum of the largest diameters of the target lesions is reduced by more than 30%, and lasts for more than 4 weeks. | 2 to 6weeks after the end of treatment | 
| Percentage of participants achieving remission (PR+CR) and lesion stabilization (SD) after treatment | Disease control rate (DCR) is the percentage of participants who achieve remission (PR+CR) and stabilization of lesions (SD) after the treatment. Stable disease (SD) means that the sum of the largest diameters of the tumor lesions has not shrunk to PR, or has not enlarged to PD. | 2 to 6weeks after the end of treatment | 
| 2-year progression-free survival (PFS) rate | Percentage of participants who survived or were free of tumor progression from enrollment to the second year of follow-up. | From enrollment to study completion, assessed up to 2 years | 
| 3-year overall-survival (OS) rate | Percentage of participants who survived from enrollment to the third year of follow-up. | From enrollment to study completion, assessed up to 3 years | 
| Number of participants with treatment-related adverse events as assessed by NCI-CTC | Toxicity deaths and early withdrawal from treatment due to toxic effects will be described. Toxicity assessment of adverse events and serious adverse events (SAEs) using the NCI-CTC. | From enrollment to study completion, assessed up to 3 years |