Conversion Therapy of Fruquintinib in Combination With Sintilimab and SOX in Unresectable Gastric Cancer

Study Overview
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Brief Summary
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This is a phase II study to evaluate the efficacy and safety of combination of fruquintinib (VEGFR 1/2/3 inhibitor), sintilimab (PD-1 inhibitor) and SOX conversion therapy in unresectable advanced gastric cancer patients.

Detailed Description
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Eligible patients will be given 3 or 6 cycles of combined therapy of fruquintinib + sintilimab + SOX. Then the patients evaluated resectable will be given one additional cycle of combined treatment with sintilimab + SOX, followed by R0 resection. If evaluated unresectable after 6 cycles of combination therapy, the patient will be given palliative first-line treatment. Adjuvant treatment with SOX regimen will be started 4 weeks after R0 resection for a total of 8 cycles in the perioperative period.

Official Title
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A Phase II Clinical Study of Fruquintinib Combined With Sintilimab and SOX as Conversion Therapy of Potentially Resectable Stage IV Gastric Cancer

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: fruquintinib + sintilimab + SOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed the Informed Consent Form Ages: 18-75 Years (concluding 18 and 75 Years) Pathologically confirmed gastric/gastroesophageal junction adenocarcinoma, and meets one of the following conditions: invasion of adjacent organs such as colon, tail of pancreas and spleen; localized peritoneal metastasis; positive exfoliative cytology of ascites; class I, class II, part of class III and very few class IV stage IV gastric adenocarcinoma according to biological behavior; N3; extensive or fused lymph node metastasis; Krukenberg tumor; Liver metastasis limited to one lobe, less than 5cm in diameter, isolated abdominal aortic metastasis, etc; Untreated(e.g. radiotherapy, chemotherapy, target therapy and immunotherapy) Life expectancy greater than 3 months ECOG(Eastern Cooperative Oncology Group) :0 1 Sufficient organ and bone marrow functions as follows: Absolute Neutrophil Count (ANC) ≥1.5×109/L, White Blood Cell≥3.5×109/L; Platelet Count of ≥100×109/L; Hemoglobin≥90g/L; Total Bilirubin (TBIL) ≤1.5 x ULN; ALT and AST<2.5 x ULN, GPT≤1.5×ULN; If there is liver metastasis, then ALT and AST<5.0 x ULN, GPT≤3.0×ULN; Serum Creatinine (SCr) ≤1.0×ULN; Endogenous creatinine clearance rate > 60ml / min (Cockcroft Gault formula); No severe dysfunction of heart, lung and liver; No jaundice and gastrointestinal obstruction; No acute infection Not participating in other clinical trials 4 weeks before and during the treatment Exclusion Criteria: Known HER-2 positive Distal metastasis to lung, brain, and bone Have received operation on the stomach A history of other malignancies within 5 years prior to inclusion, except for cervical carcinoma in situ, basal or squamous cell skin cancer Patients with any active autoimmune disease or a documented history of autoimmune disease within 4 weeks prior to enrollment Previously received allogeneic bone marrow transplantation or organ transplantation Known hypersensitivity to any of the study drugs or excipients Hypertension that is not controlled by the drug, and is defined as: SBP ≥150 mmHg and/or DBP ≥90 mmHg International normalized ratio (INR) > 1.5 or partially activated prothrombin time (APTT) > 1.5 × ULN Poorly controlled diabetes before enrollment Clinically significant electrolyte abnormalities judged by researchers With any diseases or conditions that affected drug absorption, or the patient could not take drugs orally Patients with obvious evidence of bleeding tendency or medical history within 3 months before enrollment, hemoptysis or thromboembolism within 12 months Cardiovascular diseases with significant clinical significance, including but not limited to acute myocardial infarction, severe / unstable angina pectoris or coronary artery bypass grafting within 6 months before enrollment; Congestive heart failure, New York Heart Association (NYHA) grade > 2; ventricular arrhythmia requiring drug treatment; LVEF (left ventricular ejection fraction) < 50% Active infection or serious infection that is not controlled by drug (≥CTCAE v5.0 Grade 2） History of clinically significant hepatic disease, including, but not limited to, known hepatitis B virus (HBV) infection with HBV DNA positive (copies ≥1×104/ml); known hepatitis C virus infection with HCV RNA positive (copies ≥1×103/m) Women who are pregnant or lactating Urinary protein ≥ ++, and the 24-hour urine protein quantification is greater than 1.0 g Have any other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other conditions which, according to judgement of the investigator, renders the patient inappropriate for using of the investigational product or may affect interpretation of study results Patients considered unsuitable for inclusion in this study by the investigator.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>fruquintinib + sintilimab + SOX (S-1 + oxaliplatin) | Drug: fruquintinib + sintilimab + SOX<br>* fruquintinib: 4mg/d, qd po, d1-14, q3w; sintilimab: 200 mg/d, IV d1, q3w; S-1: BSA<1.25 m2, 40mg twice/day; BSA1.25-1.5m2, 50mg twice/day; BSA≥1.5 m2, 60mg twice/day, po, d1-14, q3w; oxaliplatin: 130mg/m2, ivgtt 2-6h, d1, q3w<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical complete resection rate (R0) | This is a complete macroscopic resection of the gross tumor with negative surgical margins | about 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of downstaging | To determine the rate of downstaging of locally advanced cT3-4 and/or N+ gastric carcinomas after preoperative therapy | about 3 years | 
| Pathological complete response (pCR) rate | pCR is defined as the absence of residual tumor based on evaluation of the resected esophagogastric specimen according to Becker remission criteria | about 3 years | 
| Major pathological response (MPR) | MPR is defined as less than 10% residual tumor after neoadjuvant therapy | about 3 years | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of the participants in the analysis population who had a confirmed CR or PR according to RECIST 1.1 based on investigator assessment. | about 3 years | 
| Progression-free survival (PFS) | Progression-free survival (PFS) [time frame: from the initial date of neoadjuvant therapy to the date of first documentation of disease progression or death due to any cause, whichever occurs first. Patients without an event prior to the time of analysis will be censored at the last assessment that is stable disease (SD) or better]. Progression is defined according to RECIST v1.1. Estimated using Kaplan-Meier method. | about 3 years | 
| Overall survival (OS) | Overall survival (OS) [time frame: from the initial date of neoadjuvant therapy to the date of death due to any cause. Patients without documentation of death at the time of analysis will be censored at the last follow-up date]. Estimated using Kaplan-Meier method. | about 3 years | 
| adverse event (AEs) | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | about 3 years |