Toripalimab Combined With Chemotherapy as Neoadjuvant Treatment of Gastric Cancer

Study Overview
=================
Brief Summary
-----------------
Gastric cancer (GC) is one of the most common malignancies. According to the global cancer statistics 2018, there were 1,033,701 new cases of gastric cancer per year, ranked the fifth place in new tumors, and 782,685 deaths, ranked the second place in cancer deaths. At present, surgery is the only way to cure gastric cancer, but the 5-year survival rate is only 20%-30%. studies have confirmed that neoadjuvant therapy could improve the R0 resection rate and overall survival, which is considered a better treatment strategy. PD 1 monoclonal antibody is definitely effective in neoadjuvant therapy in other tumors such as NSCLC and bladder cancer, especially in PD-L1+ patients. However, there is no research of PD-1 monoclonal antibody in neoadjuvant therapy of gastric cancer. Thus we plan to conduct this prospective phase II clinical trial, evaluating the safety and efficacy of toripalimab, also known as JS001, in combination with XELOX for the neoadjuvant therapy of gastric cancer.

Detailed Description
-----------------
This phase II trial is a single-arm, open Label, non-randomized and single-center clinical study. Patients who met the study criteria will receive the combination of toripalimab (240 mg d1) with XELOX (oxaliplatin 130 mg/m2 QD, d1, capecitabine 1000 mg/m2 BID, d1-d14) of a 3-week treatment cycle up to two cycles. After the second cycle of treatment, clinical efficacy evaluation will be done by MDT according to iRECIST. For patients with CR/PR/SD, surgery will be performed within 4 weeks. For patients with disease progress, MDT will determine whether the surgery could be performed. If resection could not be done, the patients would receive Original chemotherapy with toripalimab for 1 more cycle, chemoradiotherapy or the second line chemotherapy. The primary endpoint is Major pathological response.

Official Title
-----------------
A Phase II Study of XELOX and Toripalimab in the Neoadjuvant Treatment of Stage II/III Gastric or GE Junction Adenocarcinoma

Conditions
-----------------
Gastric Cancer Stage II, Gastric Cancer Stage III

Intervention / Treatment
-----------------
* Drug: Toripalimab
* Drug: oxaliplatin
* Drug: capecitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, siwert type I was excluded. Clinical determined T3/4 N any or T 1/2 N 2/3 referred to AJCC 8, based on CT, gastroscopy, endoscopic ultrasound, gastrointestinal angiography, general ultrasound, or laparoscope if the patient can afford. No prior chemotherapy and/or immunotherapy and/or radiation therapy. Age 18 to 75 years old. ECOG 0 or 1 . Adequate Organ Function Laboratory Values Hb≥90g/L, WBC≥3.5×109 /L, ANC≥1.5×109 /L, Platelets≥100×109 /L Serum creatinine ≤1.0×ULN ALT≤1.5 ×UNL , AST ≤1.5×ULN，ALP≤ 1.5 ×ULN Serum total bilirubin ≤1.5 × ULN Signed Informed consent Exclusion Criteria: Pathology types other than adenocarcinoma, such as squamous cell carcinoma. intra-abdominal dissemination or distant metastasis (M1). Digestive tract obstruction or repeated bleeding which can not be controlled, clinically significant ascites. Those who cannot swallow pills. Cirrhosis caused by any cause. Heart function NYHA > I degree Previous myocardial infarction, unstable angina, stroke and uncontrolled arrhythmia. with any contraindications for surgery. Previously received chemotherapy and or radiation therapy. Previously received any anti-PD 1 , anti - PD L1/L2 antibodies, anti-CTLA 4 antibodies and other immunotherapy. Previously received other anti-tumor treatments. History of surgical resection for gastric cancer. Have had other tumors in the past, except for cured skin cancer and cervical cancer in situ. Accompanied by systemic diseases which cannot meet the conditions of chemotherapy. Pregnancy and lactating patients. History of mental diseases. Poor compliance. Active central nervous system (CNS) metastases and/or carcinomatous meningitis. History of gastrointestinal perforation and/or fistula in the past 6 months; history of intestinal obstruction (including incomplete intestinal obstruction which need for extraintestinal Nutritional); inflammatory bowel disease or extensive bowel resection(Partial colon resection or extensive small Intestinal resection complicated with chronic diarrhea);Crohn's disease; ulcerative colitis or chronic diarrhea. History of interstitial pneumonia, drug-induced pneumonia, idiopathic pneumonia or active pneumonia. Active tuberculosis (TB), undergoing anti-tuberculosis treatment or within 1 year before the first dose has infected Human immunodeficiency virus (HIV1 / 2 antibody positive). Has known active hepatitis B or hepatitis C. Acute or chronic active hepatitis B or hepatitis C virus infection, hepatitis B virus (HBV) DNA > 2000 IU / ml or 10^4 copies / ml; Hepatitis C virus (HCV) RNA > 10^3 copies / ml ; hepatitis B surface antigen(HbsAg) and anti-HCV antibody is positive at the same time. Severe infections active or poorly controlled. Severe infections within 4 weeks before the first dose, includes but not limited to hospitalization attributed to infection, bacteremia or severe pneumonia complications. Active autoimmune disease requiring systemic treatment or the history within 2 years (one with vitiligo, psoriasis, alopecia or Graves' disease not requiring systemic treatment in the last 2 years, hypothyroidism only requiring thyroid hormones alternative treatment and type 1 diabetes only requiring insulin replacement therapy can be enrolled). Have has known history of primary immunodeficiency. patients with positive autoimmune antibodies only will need to be confirmed the presence of autoimmune diseases according to the investigator's judgment. Application of immunosuppressive drugs within the latest 4 weeks, excluding nasal glucocorticoids and topical glucocorticoids by inhaling or other routings. Physiological doses of systemic glucocorticoids (prednisone not exceeding 10 mg/day or equivalent dose of other glucocorticoids) and temporary use of glucocorticoids for the treatment of dyspnea caused by asthma, chronic obstructive pulmonary disease and other diseases would be allowed. have received live attenuated vaccines within 4 weeks or intend to be vaccinated during the study period. have received systemic immunostimulant treatment within 4 weeks. Have undergone major surgery (such as craniotomy, thoracotomy or laparotomy) within 4 weeks, or unhealed wound, ulcer or fracture at present. Have uncontrolled metabolic disorders , other non-malignant tumors, systemic diseases or secondary reactions originated from the cancer which may lead to higher medical risks and/or the uncertainty of survival evaluation. patients with other acute or chronic diseases, psychiatric disorders, or abnormal laboratory tests that may lead to the increasing risk of participating the research and drug administration, or interference results Interpretation, whom may be excluded from the study according to the investigator's judgment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XELOX combined with Toripalimab<br> | Drug: Toripalimab<br>* toripalimab 240 mg d1; q3w, up to two cycles.<br>Drug: oxaliplatin<br>* oxaliplatin 130 mg/m2 QD, d1,q3w, up to two cycles<br>Drug: capecitabine<br>* apecitabine 1000 mg/m2 BID, d1-d14 ,q3w, up to two cycles<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major pathological response rate | Proportion of subjects with residual tumor less than 10% or complete response | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incicende of Adverse Events (AEs) | Number of patients with AE, treatment-related AE (TRAE), immune-related AEs (irAE), AE of special interest (AESI), serious adverse event (SAE) assessed by CTCAE v5.0. | Up to 6 months | 
| Pathologic Complete Response (pCR) Rate | Proportion of subjects with absence of viable tumor on surgical resection specimen as determined by local pathology review. | Up to 6 months | 
| Overall Response Rate (ORR) | Proportion of subjects with initial RECIST 1.1 measurable disease who have complete response (CR) or partial response (PR) according to iRECIST | Up to 6 months | 
| Disease Free Survival (DFS) | Time from Cycle 1 Day 1 treatment administration to the first documented event of: disease progression, disease recurrence following surgery (preferably biopsy proven), or death - whichever occurs first. | Up to 5 years | 
| Overall Survival (OS) | Time from Cycle 1 Day 1 treatment administration to death due to any cause. | Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
JS001, Toripalimab, Gastric Cancer, neoadjvant chemotherapy