Clinical trial NCT05545436: Carrelizumab (PD-1) Combined With Chemotherapy in Neoadjuvant Treatment of Locally Advanced Gastric Cancer
Official title: A Single-center Prospective Single-arm Study of the Efficacy of Carrelizumab (PD-1) Combined With Chemotherapy in Neoadjuvant Treatment of Locally Advanced Gastric Cancer and Its Effect on Tumor Immune Microenvironment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Locally Advanced Gastric Cancer
Lead sponsor: Third Affiliated Hospital, Sun Yat-Sen University
Sponsor class: OTHER
Collaborators: name: Jiangsu Hengrui Pharmaceutical Co., Ltd.
First posted: 2022-09-19
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single-arm, open, exploratory clinical study to evaluate the efficacy of carrelizumab (PD-1) combined with chemotherapy (SOX/XELOX) as neoadjuvant therapy and to observe the changes of tumor immune microenvironment in patients with locally advanced gastric or gastroesophageal junction cancer (T3-4NXM0).

Detailed description: For advanced gastric cancer, standard treatment is D2 gastrectomy combined with perioperative medications, when the tumor is infiltrating into submucosa, around or with lymph node metastasis, and can reduce the success rate of surgery, previous studies have showed a tumor on perioperative chemotherapy helps to drop period, and improve the long-term survival of patients, compared with surgery alone, It can improve the 5-year overall survival (OS) by about 10%. At present, SOX protocol is recommended as the perioperative protocol for advanced gastric cancer in domestic guidelines \[5\]. However, for patients with T3/T4 or positive lymph node (N+), the probability of recurrence or metastasis after resection is high, and the 5-year survival rate is only 23%. Previous studies have found that the prognosis of patients with complete pathological response or near complete pathological response after neoadjuvant chemotherapy is significantly improved, whereas the pCR rate is only less than 10%. It is an effective way to improve the prognosis of gastric cancer patients to seek neoadjuvant therapy that can improve the pathological response rate. Chemotherapy and immune checkpoint inhibitor drugs have a synergistic mechanism on the theoretical basis. Pd-1 inhibitors are a kind of immune checkpoint inhibitors. In the process of "immune escape" of tumors,PD-1 inhibitors are involved in the activation process of the immune system, and by inhibiting PD-1 receptors, T cells can be activated normally. Thus, the immune system of the body can promote the killing of tumor cells.

Our research group plans to carry out the study of carrelizumab (PD-1) combined with SOX/XELOX chemotherapy as a neoadjuvant therapy in locally advanced gastric cancer. A total of 34 patients with locally advanced gastric or gastroesophageal junction carcinoma of T3-4NXM0 were enrolled. After 3 cycles of carrelizumab (PD-1) combined with chemotherapy, radical resection was performed, and the treatment effect was evaluated by pathological remission of the surgical tissue. Collection and treatment of gastroscope biopsy tissue samples before and after neoadjuvant therapy surgery samples: 1. The multiple fluorescent immunohistochemical (mIHC) technique were used to detect the immune cells in tumor tissue infiltration, compared neoadjuvant therapy after curative effect before treatment between patients with good and poor effects of immune cell infiltration, the difference between a explore treatment response and the correlation between the baseline immune microenvironment; To compare the changes of immune cell infiltration before and after treatment, and to explore the effect of combined immunotherapy on the immune microenvironment of locally advanced gastric cancer. 2. High-throughput sequencing technology was used to sequence DNA molecules to compare the pre-treatment gene sequences between patients with good and poor efficacy after neoadjuvant therapy, and to explore the correlation between the effect of neoadjuvant therapy and gene sequence changes (dMMR, MSI, TMB, PD-L1, etc.).

Eligibility criteria: Inclusion Criteria:

1. T3-4NxM0 locally advanced gastric or gastroesophageal junction carcinoma was confirmed by gastroscopic biopsy, CT and pathological examination;
2. No previous systematic treatment for the current disease;
3. Age ≥ 70 years, age ≥18 years, both sexes;
4. ECOG physical status score 0-1; Full organ and bone marrow function:
5. Blood routine: hemoglobin ≥90g/L, neutrophil count ≥1.5×10\^9/L, platelet count ≥75×10\^9/L; Liver function: serum total bilirubin ≤1.5× upper normal value (UNL), aspartate transferase ≤3×UNL, alanine Acid transferase ≤3×UNL; Renal function: serum creatinine ≤1.5×UNL, creatinine clearance rate ≥50ml/min; Coagulation function: INR, APTT and PT ≤1.5×UNL; Serum albumin ≥30g/L; Thyrotropin (TSH) and free thyroxine (fT4) were within the range of normal ±10%.

   Electrocardiogram showed no obvious abnormality.
6. Not receiving blood transfusion, blood products, or blood cell growth factors such as granulocyte colony-stimulating factor within 2 weeks;
7. Sign an informed consent form before starting the study on a specific screening procedure;
8. The estimated survival time is more than 3 months;
9. Subjects volunteered to join this study, with good compliance, safety and survival follow-up -

Exclusion Criteria:

Patients with any of the following were excluded from the study:

1. People with allergic disease, history of severe drug allergy, known allergy to macromolecular protein preparations or carrelizumab;
2. Early gastric cancer;
3. Gastric cancer patients with HER2 amplification by pathological gene detection;
4. History of other malignancies (except cured basal cell carcinoma of the skin, cured cervix) with disease-free survival \<5 years Carcinoma in situ and gastrointestinal neoplasms proven to be cured by endoscopic mucosal resection);
5. The presence or history of any active autoimmune disease (including but not limited to: interstitial pneumonia, Uveitis, enteritis, nephritis, hyperthyroidism, hypothyroidism);
6. You are using immunosuppressive agents or hormone therapy (systemic or topical) to achieve immunosuppression, and Continued to use within 2 weeks before enrollment;
7. Severe infection (if intravenous antibiotics, antifungal or antiviral drugs are needed);
8. Congenital or acquired immune deficiency (such as HIV-infected persons), or active hepatitis ((with regular antiviral treatment)

Primary outcomes:
measure: Pathological complete response rate (pCR, Becker criteria, TRG 1A)
timeFrame: Up to approximately 6 months.
Secondary outcomes:
measure: Major pathological response rate (MPR, TRG1a/ B)
timeFrame: Up to approximately 6 months.
measure: R0 resection rate and objective response rate (ORR, RECIST 1.1)
timeFrame: Up to approximately 6 months.
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The Third Affiliated Hospital of Sun Yat-sen University
state: Guangdong
Study officials:
affiliation: Third Affiliated Hospital, Sun Yat-Sen University
name: Hongbo Wei, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: