Conversion Therapy of Sintilimab in Combination With Apatinib and Chemotherapy in Stage IV Gastric Cancer

Study Overview
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Brief Summary
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This is a single-arm, phase II study aiming to evaluate the feasibility and efficacy of sintilimab (PD-1 inhibitor) in combination of apatinib and two-drug chemotherapy (S-1 plus nab-paclitaxel) as conversion therapy in patients with stage IV gastric cancer in China.

Official Title
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Efficacy and Safety of Conversion Therapy With Sintilimab in Combination With Chemotherapy and Apatinib in Patients With Stage IV Gastric Cancer

Conditions
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Gastric Cancer Stage IV

Intervention / Treatment
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* Drug: sintilimab
* Drug: apatinib
* Drug: S1
* Drug: Nab paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: gastric adenocarcinoma confirmed by gastroscopy and pathology (histologically/cytologically ) ; life expectancy of ≥3-month； unresectable patients who were initially diagnosed as stage IV (clinical stage, American Joint Committee on Cancer 8th edition); Eastern Cooperative Oncology Group performance status: 0-1; must have at least 1 of the following unresectable factors indicated by CT, MRI or positron emission tomography(PET)-CT: N3 lymphatic metastasis; Extensive or bulky lymph nodes; T4b; Hepatic metastasis: ≤5 lesions, total diameter of ≤8cm; Peritoneal metastasis (CY1, P1); Kukernburg tumor; adequate organ function; pregnant test negative of females of childbearing potential , and willing to use adequate contraception; written Informed Consensus Form; Exclusion Criteria: prior use of any checkpoint inhibitor treatment, including PD-1, programmed cell death ligand-1(PDL-1), CTLA4 etc; Her-2 positive with willing to use herceptin treatment; prior active autoimmune disease or history of autoimmune disease; clinically significant cardiovascular and cerebrovascular diseases, including but not limited to severe acute myocardial infarction within 6 months before enrollment, unstable or severe angina, or coronary artery bypass surgery, Congestive heart failure (New York heart association (NYHA) class > 2), ventricular arrhythmia which need medical intervention, left ventricular ejection fraction(LVEF) < 50%; not controlled hypertension; prior systemic treatment to metastatic disease； previous digestive tract bleeding history within 3 months or evident gastrointestinal bleeding tendency; history of immunodeficiency including seropositivity for human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease, or active hepatitis ; patients who may receive vaccination during study period; mental disorders history, or psychotropic drug abuse history; unable to orally administration;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: eligible patients will be given treatment of sintilimab, apatinib and chemotherapy (nab-paclitaxel) every 3 weeks
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment<br>Eligible patients will be given sintilimab(200mg iv, day 1), apatinib(250mg,once daily), S-1 (60mg, twice daily, day1-14) and nab-paclitaxel(without peritoneal metastases: 260 mg/m^2 iv for 3h; with peritoneal metastases: 200mg/m^2 iv plus 60mg/m^2 ip; day 1) every 3 weeks for at least 3 cycles. The feasibility of surgery will be evaluated by a multidisciplinary team every 2-4 cycles. Patients assessed as inoperable will be allowed to continue maintenance therapy with the original regimen until disease progression or intolerable toxicity. For patients assessed as operable, apatinib will be discontinued and one more cycle of sintilimab combined with S-1 and nab-paclitaxel will be administered; radical surgery will be performed within 2-4 weeks after the end of treatment. Safety run-in stage will be set in the first 6 patients to determine the safety. The study will be terminated if dose-limiting toxicities (DLTs) occur in more than 2 patients. | Drug: sintilimab<br>* a checkpoint inhibitor via blocking PD-1 (programmed cell death-1) site of signaling.<br>* Other names: Tyvyt;Drug: apatinib<br>* a multi-target anti-angiogenic tyrosine kinase inhibitor (TKI)<br>Drug: S1<br>* S-1 is an oral fluoropyrimidine consisting of tegafur (a prodrug that is converted to fluorouracil, mainly in liver microsomes but also in tumour tissue), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which degrades 5-FU), and oteracil (which inhibits the phosphorylation of 5-FU in the gastrointestinal tract, thereby reducing the toxic effects of 5-FU in the intestinum).<br>Drug: Nab paclitaxel<br>* Nab paclitaxel is a albumin-bound well tolerated paclitaxel than traditional paclitaxel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0-surgery conversion rate | The proportion of participants who underwent R0 surgery among all participants. | up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| objective response rate (ORR) | The proportion of participants who achieved complete response(CR) or partial response(PR) per Response Evaluation Criteria in Solid Tumors criteria (RECIST v1.1). | up to one year | 
| disease control rate (DCR) | The proportion of participants who achieved CR, PR or stable disease(SD) per RECIST v1.1. | up to one year | 
| conversion rate | The proportion of participants who underwent surgery among all participants. | up to one year | 
| overall survival (OS) | The time from the first dose of the study treatment to death from any cause. | up to two years | 
| event-free survival (EFS) | The time from the first dose of the study treatment to any of the following events: progression of disease, local or distant recurrence, or death due to any cause. | up to two years | 
| Treatment-Related Adverse Events (TRAEs) | The grade and proportion of participants who experienced TRAEs per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 | from the first day of treatment until 1 month after the end of treatment | 
| surgery-related complications | Incidence and grade of surgery-related complications as assessed byper the Clavien-Dindo classification | from the day of surgery to 30 days postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-1 inhibitor, conversion therapy