PD-1 Antibody Combined With Modified FLOT Regimen in the Treatment of Unresectable Locally Advanced or Limited Metastatic Gastric Cancer
PD-1 Antibody Combined With Modified FLOT Regimen in the Treatment of Unresectable Locally Advanced or Limited Metastatic Gastric Cancer
This study is to evaluate the efficacy and safety of domestic programmed death 1（ PD-1）
 antibody (Camrelizumab for injection) combined with fluorouracil plus leucovorin,
 oxaliplatin, and albumin bound paclitaxel (modified FLOT, mFLOT) regimen in the treatment of
 patients with unresectable locally advanced or limited metastatic gastric cancer. The primary
 efficacy endpoint is R0 resection rate.
This is an open, single center, prospective phase II clinical study to evaluate the efficacy
 and safety of domestic PD1 antibody (Camrelizumab for injection) combined with mFLOT regimen
 in the treatment of unresectable locally advanced or limited metastatic gastric cancer. This
 study will be carried out in our center, about 40 patients will be enrolled.

 Patients with unresectable locally advanced or limited metastatic gastric cancer who had not
 received any prior antitumor therapies were treated with domestic PD1 antibody (Caerelizumab
 for injection) commbined with mFLOT regimen, and human epidermal-growth-factor receptor 2
 (HER-2) positive patients were treated with Herceptin. The efficacy of therapy was evaluated
 every 3 treatment cycles. After 6 cycles, surgical experts evaluated the resectability of the
 tumor, and the patients who were confirmed to be resectable received surgery within 3-6 weeks
 after immunochemotherapy. The patients with good postoperative recovery continued to receive
 the same immunochemotherapy in 3-6 weeks, and totally at most 12 cycles. Patients who were
 evaluated as progressive disease (PD) at any time withdrawn from the study as conversion
 failure.Patients who did not PD at 6 cycles of treatment but did not reach the criteria for
 R0 resection, continued to receive another 3 cycles of the prior chemotherapy. If resectable
 then, surgical treatment was performed, if still unresectable, the immunochemotherapy for
 transformation was evaluated as unsuccessful. The patients were treated according to the
 principle of palliative treatment until the disease progressed or intolerable toxicity. The
 efficacy and safety will be continuously monitored and evaluated throughout the study period
 (including a 30 day follow-up period). 40 cases were expected to be enrolled: 3-4 cases per
 month, completed in 1 year and finished in 2 years.
Inclusion Criteria:

 -  Written informed consent obtained.

 -  Age ≥ 18 years at time of study entry, no gender limit.

 -  Participants must have histologically or cytologically confirmed adenocarcinoma of the
 stomach (including adenocarcinoma of the gastroesophageal junction).

 -  At least one measurable site of disease as defined by RECIST criteria with spiral CT
 scan or MRI.

 -  CT or MRI showed unresectable locally advanced gastric cancer (imaging stage T4b and /
 or second station lymph node > 3cm or fusion mass) or limited metastatic gastric
 cancer with any of the following single site metastasis:

 1. Retro-peritoneal lymph node metastasis (RPLM) (e.g. para-aortic,
 intra-aorto-caval, para-pancreatic or mesenteric lymph nodes).

 2. Single or bilateral Krukenberg tumors.

 3. No more than 5 liver metastases, and the maximum diameter of the lesions was less
 than 5 cm.

 4. Adrenal metastasis.

 5. Localized potentially operable peritoneal carcinomatosis: stage P1 according to
 classification of the"Japanese Research Society for Gastric Cancer (JRSCGC)".

 -  No clinically visible peritoneal metastasis (such as CT imaging confirmation or
 ascites).

 -  No prior anti-tumor therapy.

 -  Performance status (PS) < 2 (ECOG scale).

 -  Life expectancy of at least 12 weeks.

 -  Adequate blood count, liver-enzymes, and renal function: hemoglobin≥90g/dL,absolute
 neutrophil count ≥ 1.5×109/L, platelets ≥100 x109/L; Total bilirubin < 1.5x upper
 normal limit (UNL), Aspartate Aminotransferase (SGOT), Alanine aminotransferase (SGPT)
 <2.5 x ULN, if liver metastasis existed, SGOT,SGPT<2.5xULN. International normalized
 ratio (INR) ≤2.5 x ULN, Serum Creatinine ≤ 1 x institutional ULN or creatinine
 clearance (CrCl) >50ml/min (if using the Cockcroft-Gault formula ).

 -  Female patients with reproductive potential must have a negative urine or serum
 pregnancy test within 7 days prior to start of trial.

 -  Subject is willing and able to comply with the protocol for the duration of the study
 including undergoing treatment, adherence to contraceptive measures, scheduled visits
 and examinations including follow up.

 Exclusion Criteria:

 -  A history of other malignancies within 3 years prior to enrollment, except for
 cervical carcinoma in situ or skin basal cell carcinoma that had been cured.

 -  Accompanied with brain or meningeal metastasis.

 -  Malignant pleural and peritoneal effusion.

 -  Accompanied by gastrointestinal obstruction, gastrointestinal bleeding (fecal occult
 blood +++ )or perforation.

 -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,or anti-Cytotoxic
 T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any
 other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
 pathways).

 -  Has an active or history of autoimmune diseases (such as systemic lupus erythematosus,
 rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, multiple
 sclerosis, vasculitis, glomerulonephritis, etc.), or with high risk (such as receiving
 immunosuppressive therapy after organ transplantation), but in the past two years with
 vitiligo, psoriasis, alopecia or Graves' disease without systemic treatment,
 hypothyroidism with thyroid hormone replacement therapy only and type I diabetes only
 need insulin replacement therapy can be enrolled.

 -  Suffering from interstitial lung disease or pneumonia, pulmonary fibrosis, acute lung
 disease and radiation pneumonia.

 -  Participate in other clinical studies of drugs (subject to the use of trial drugs)
 within 4 weeks before the first administration, unless participating in observational
 (non intervention) clinical studies.

 -  Used immunosuppressive drugs within 4 weeks before the first dose of study treatment,
 excluding nasal, inhalation or other local glucocorticoids or physiological doses of
 systemic glucocorticoids (i.e. no more than 10mg prednisone or equivalent dose of
 other glucocorticoids, or short-term (no more than 7 days) use of glucocorticoids to
 prevent or treat non autoimmune allergic diseases.

 -  Planned to receive live attenuated vaccine within 4 weeks before the first dose of
 study treatment or during the study period. Note: inactivated virus vaccine for
 seasonal influenza is allowed within 4 weeks before the first administration, however,
 live attenuated influenza vaccine is not allowed.

 -  Major surgery (craniotomy, thoracotomy or laparotomy) was performed within 4 weeks
 before the first dose of study treatment, or major surgery (not in this study) was
 expected to be performed during the study treatment.

 -  A history of HIV infection (i.e. HIV antibody positive), or other acquired or
 congenital immunodeficiency diseases, or a history of organ transplantation or stem
 cell transplantation.

 -  Patients with active chronic hepatitis B or active hepatitis C, hepatitis B virus
 carriers. Stable hepatitis B after drug treatment (DNA titer not higher than 200iu/ml
 or copy number < 1000copies / ml) and cured patients with hepatitis C (HCV RNA test
 negative) can be included in the group.

 -  Active tuberculosis.

 -  Severe infection within 4 weeks before the first administration, or active infection
 within the first 2 weeks and requiring oral or intravenous antibiotic treatment.

 -  Symptomatic congestive heart failure (NYHA grade II-IV) or symptomatic or poorly
 controlled arrhythmias;

 -  Uncontrolled arterial hypertension (systolic blood pressure≥160mmhg or diastolic blood
 pressure≥100mmhg) even after standard treatment.

 -  Any arterial thromboembolism events, including myocardial infarction, unstable angina
 pectoris, cerebrovascular accident or transient ischemic attack, occurred within 6
 months before the treatment.

 -  A history of deep vein thrombosis, pulmonary embolism or any other serious
 thromboembolism within 3 months before enrollment (implantable venous infusion port or
 catheter-derived thrombosis, or superficial venous thrombosis is not considered as
 "severe" thromboembolism)

 -  Have a clear history of neurological or mental disorders in the past, such as
 epilepsy, dementia, poor compliance, or patients with peripheral nervous system
 disorders.

 -  Alcohol addicts or have a history of drug use or drug abuse in the past 1 yea.

 -  Pregnant or lactating women, fertile women without adequate contraceptive measures

 -  Other acute or chronic diseases, mental disorders, or laboratory test value
 abnormalities that may result in increased risk associated with study participation or
 drug administration, or interference with the interpretation of the study results, and
 the patient, in the judgment of the investigator, is not eligible to participate in
 the study.