Lenvatinib Plus Tislelizumab and CapeOX as First-Line Treatment for Advanced GC/GEJC With Positive PD-L1 and Low TMEscore

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, prospective, phase II clinical study to evaluate the efficacy and safety of intensive treatment with lenvatinib plus tislelizumab and CapeOX as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma with PD-L1 positive and low TMEscore. A total of 92 subjects are randomly divided into study group and control group according to 1:1 ratio. Tislelizumab 200mg, iv, d1+ oxaliplatin 130mg/m2, iv, d1+ capecitabine 1000mg/m2, bid po, D1-14, q3w ± Lenvatinib 8mg, qd po regimen are received, respectively (3 weeks as a cycle, a maximum of 8 cycles of treatment). Then the maintenance treatment phase with tislelizumab ± lenvatinib is entered, and the specific dosage is the same as the treatment period. Effectiveness is assessed every 9 weeks (±7 days) until disease recurrence, metastasis, death, or loss of follow-up. The primary endpoint of this study was PFS, and secondary endpoints were OS, ORR, DoR, and DCR.

Official Title
-----------------
Tislelizumab Plus CapeOX ± Lenvatinib as First-Line Treatment for Advanced GC/GEJC With Positive PD-L1 and Low TMEscore: A Multi-center, Prospective, Phase II Study

Conditions
-----------------
Gastric Cancer

Intervention / Treatment
-----------------
* Drug: lenvatinib and tislelizumab plus CapeOX chemotherapy
* Drug: tislelizumab plus CapeOX chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients voluntarily participated in the study, signed the informed consent, and had good compliance; Age over 18 (including 18 years old), gender is not limited; Histologically and/or cytologically confirmed advanced gastric cancer or gastroesophageal junction adenocarcinoma (stage IV); Tumor with PD-L1 positive and low tumor microenvironment score (TMEscore) Have not received systemic antitumor therapy before; Or have previously received adjuvant or neoadjuvant therapy (chemotherapy/radiotherapy) for the purpose of cure, and the time of tumor recurrence > 6 months since the last treatment ECOG performance status of 0-2 points; Expected survival ≥12 weeks; Blood test (without blood transfusion within 14 days) 1) Neutrophil absolute value ≥1.5×10^9/L, platelet ≥100×10^9/L, hemoglobin ≥90g/L); 2) Liver function test (aspartate aminotransferase and glutamate aminotransferase ≤3×ULN, bilirubin ≤1.5×ULN; In case of liver metastasis, AST and ALT≤5×ULN); 3) Renal function (serum creatinine ≤1.5×ULN, or creatinine clearance (CCr)≥60ml/min); Men and women of childbearing age must use effective contraceptive methods. Exclusion Criteria: Previously received therapy that targets T cell co-stimulation or checkpoint pathways ,such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, etc.; Previously received anti-vascular small-molecule targeted drug therapy, such as fuquinitinib, regofenib, etc.; Received major surgery within 4 weeks prior to the first drug administration; radiotherapy, radiofrequency ablation and other investigational drugs for tumors within 2 weeks; Received live vaccine within 4 weeks prior to the first drug administration (except inactivated viral vaccine for seasonal influenza); A history of severe intolerance to drugs involved in the study (i.e., grade 4 toxicity of one of these drugs; Class 3-4 toxicity of other co-administered drugs is not excluded); Known allergy to the study drug or any of its excipients; HER2 positive gastric cancer or gastroesophageal junction adenocarcinoma; The patient had other malignancies within the previous 5 years or at the same time (except cured basal cell carcinoma, stage I squamous cell carcinoma, in situ carcinoma, intramucosal carcinoma, and superficial bladder cancer); Known brain or meningeal metastases; Patients who are preparing for or have previously received an organ or bone marrow transplant; A history of human immunodeficiency virus (HIV) infection; A history of psychotropic substance abuse or drug use; Condition that may interfere with the detection and management of suspected drug-related pulmonary toxicity, such as interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, or severe impairment of lung function; Known active or suspected autoimmune disease (except for patients with stable disease at enrollment who do not require systemic immunosuppressive therapy); Patients who required systemic corticosteroids (> 10 mg/ day efficacy dose of prednisone) or other immunosuppressive agents within 2 weeks prior to initial administration or during the study period. However, adrenal hormone replacement therapy with topical or inhaled steroids, or a therapeutic dose of prednisone ≤ 10mg/ day in the absence of active autoimmune disease was permitted; Any active infection that requires systematic anti-infective treatment occurs within 2 weeks prior to the first dose (expect prophylactic antibiotic therapy, such as for urinary tract infections or chronic obstructive pulmonary disease); Active heart disease, including myocardial infarction, severe/unstable angina in the 6 months prior to treatment. Echocardiography showed that the left ventricular ejection fraction was less than 50%, indicating poor arrhythmia control. Obvious clinical bleeding symptoms or obvious bleeding tendency and hemoptysis within 3 months prior to treatment. Or treatment of venous/venous thrombosis events within the preceding 6 months, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism; Long-term anticoagulant therapy with warfarin or heparin, or long-term antiplatelet therapy (aspirin ≥300 mg/day or clopidogrel ≥75 mg/day) is required; Any other disease, a clinically significant metabolic abnormality, abnormal physical examination or abnormal laboratory examination, for which, in the investigator's judgment, there is reason to suspect that the patient has a disease or condition unsuitable for the use of the investigational agent; Anything that, in the investigator's opinion, could put subjects receiving the study drug at risk, interfere with the study drug, subject safety assessment, or interpretation of the results; Pregnant or lactating women or women who may become pregnant.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intensive treatment of lenvatinib and tislelizumab plus CapeOX chemotherapy<br>Efficacy of lenvatinib and tislelizumab plus CapeOX as first-line treatment | Drug: lenvatinib and tislelizumab plus CapeOX chemotherapy<br>* Tislelizumab 200mg, iv, d1+ oxaliplatin 130mg/m2, iv, d1+ capecitabine 1000mg/m2, bid po, D1-14, q3w + Lenvatinib 8mg, qd po regimen are received, respectively (3 weeks as a cycle, a maximum of 8 cycles of treatment). Then the maintenance treatment phase with tislelizumab + lenvatinib is entered, and the specific dosage is the same as the treatment period.<br>|
| Active Comparator: Conventional treatment of tislelizumab plus CapeOX chemotherapy<br>Efficacy of tislelizumab plus CapeOX as first-line treatment | Drug: tislelizumab plus CapeOX chemotherapy<br>* Tislelizumab 200mg, iv, d1+ oxaliplatin 130mg/m2, iv, d1+ capecitabine 1000mg/m2, bid po, D1-14, q3w regimen are received, respectively (3 weeks as a cycle, a maximum of 8 cycles of treatment). Then the maintenance treatment phase with tislelizumab is entered, and the specific dosage is the same as the treatment period.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Defined as the time between the onset of PD or death when a patient first receives the study drug, whichever occurs first | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Defined as the time between the patient's first receipt of the study drug to death | 3 years | 
| Objective Response Rate (ORR) | Defined as the proportion of patients who achieved complete response (CR) or partial response (PR) | 3 years | 
| Disease Control Rate (DCR) | Defined as the proportion of patients achieving CR, PR, or stable disease (SD). | 3 years | 
| Duration of response (DoR) | Defined as the time between when a patient first reaches CR or PR to PD | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lenvatinib, Tislelizumab, First-line treatment, GC/GEJC, TME score, PD-L1 positive