A Sequential Trial of Low-Dose Radiotherapy Followed by Concurrent Immunotherapy, Systemic Chemotherapy, and Intraperitoneal Perfusion in Gastric Cancer With Peritoneal Carcinomatosis
調査の概要
状態
詳細な説明
In China, most gastric cancer patients are diagnosed at an advanced stage. The peritoneum is the most common site of metastasis for gastric cancer, representing a specific mode of metastasis. Based on cytology of abdominal cavity dropout cells and peritoneal implantation formation, it can be classified into CY1P0, CY1P1, and CY0P1 types. Approximately 20% of patients are diagnosed with peritoneal metastasis preoperatively or intraoperatively, and more than 50% of T3 and T4 stage patients develop peritoneal metastasis after radical surgery. Peritoneal metastasis often leads to malignant ascites, intestinal obstruction, cancer pain, and other complications, severely affecting the quality of life of patients. According to epidemiological data, in 2020, the number of gastric cancer patients with peritoneal metastasis in China reached 523,937 cases 3-6 months, and a 5-year survival rate of less than 2% . Effective control of ascites in gastric cancer patients can not only improve their quality of life but also effectively extend their survival time. The survival period for first-line gastric cancer patients with peritoneal metastasis has increased from 3-6 months with traditional chemotherapy to 12-22 months with comprehensive treatment , but the efficacy for second-line gastric cancer patients with peritoneal metastasis remains limited, and more effective treatment regimens are still needed.
Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis and ascites formation in peritoneal metastases. Research evidence shows that intraperitoneal infusion of anti-VEGF drugs, such as bevacizumab, can effectively control ascites and prolong the time to ascites recurrence. When combined with the immune checkpoint inhibitor sintilimab, the ascites control rate can reach 91%, with partial reduction of peritoneal metastases by more than 30% in some patients. Analysis of immune cells in ascites showed that the CD8+/Treg ratio increased threefold after treatment (P<0.01), and immunohistochemistry results from peritoneal biopsy indicated upregulation of PD-L1 expression in the combination therapy group (combination group vs baseline: +45% vs +10%), suggesting that blocking VEGF can normalize tumor vasculature, reverse the immunosuppressive microenvironment, enhance T-cell infiltration, and exert synergistic effects study, are actively exploring whether combining immunotherapy with VEGFR inhibitors and chemotherapy can improve survival, but further investigation is still needed.
Recent research findings indicate that low-dose radiation therapy (Low-Dose Radiation, LDR, single dose ≤1 Gy) exhibits distinct biological effects compared to conventional radiation therapy (fractionated dose1.8-3 Gy)20.LDR not only does not cause significantDNA double-strand breaks and apoptosis but also remodels the tumor microenvironment by activating various immune-related pathways.
Based on the aforementioned background, this study proposes an innovative combination therapy strategy: low-dose radiotherapy (LDR) followed by immunochemotherapy. The core mechanisms are as follows: (1) Immune initiation effect: LDR acts as an "immune initiator," inducing immunogenic cell death and activating antigen-presenting cells. The peak of immune activation occurs 24-72 hours after LDR, during which administration of the PD-1 inhibitor (serplulimab) can maximize synergistic effects. (2) Vascular normalization window: A peak in vascular normalization is observed 7-14 days after LDR treatment. Combining anti-VEGF drugs (bevacizumab analog) can maintain the vascular normalization state and improve the distribution of chemotherapeutic drugs in metastases to the peritoneum. (3) Overcoming chemotherapy resistance: LDR downregulates the expression of DNA repair genes in tumor cells, enhancing the cytotoxic action of irinotecan and albumin-bound paclitaxel. Preclinical studies show that 0.5 Gy radiotherapy can increase the concentration of paclitaxel in metastases to the peritoneum by 2.8 times.
This study selected low-dose radiotherapy combined with intraperitoneal infusion of bevacizumab. Based on whether first-line chemotherapy regimens included intravenous chemotherapy with albumin-bound paclitaxel, patients were chosen to receive second-line systemic treatment with irinotecan/albumin-bound paclitaxel combined with serplulimab. The study explores the approach of immune rechallenge and low-dose radiotherapy sequential systemic treatment combined with intraperitoneal infusion therapy, aiming to provide new therapeutic strategies and methods for second-line patients with gastric cancer accompanied by peritoneal metastasis.
研究の種類
入学 (推定)
段階
- フェーズ2
連絡先と場所
研究連絡先
- 名前:Qi Xu, Master
- 電話番号:+86-15205813046
- メール:zjhzxuqi@163.com
研究場所
-
-
Zhejiang
-
Hangzhou、Zhejiang、中国、310022
- Zhejiang Cancer Hospital
-
コンタクト:
- Qi Xu
- 電話番号:15205813046
- メール:zjhzxuqi@163.com
-
-
参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
Inclusion Criteria:
1. Age >18 years on the day of signing the Informed Consent Form; 2. The subject is able to comprehend the procedures and methods of this clinical study, and voluntarily signs the informed consent form after providing full informed consent.
3. Gastric or gastroesophageal junction adenocarcinoma (HER2-negative) confirmed by histology or cytology.
4. Imaging confirmed metastases to peritoneum (PCI score ≥10), not suitable for radical excision 5. Failure of first-line platinum-based chemotherapy (due to progression or inability to tolerate).
6. CT imaging or PET CT suggests metastases to the peritoneum, or ascites cytology is positive.
7. ECOG PS 0-2, expected survival ≥3 months. 8. Organ function meets the following criteria (within 10 days of first receiving the investigational medicinal product).
- Hematology: Platelet count ≥100×10⁹/L, hemoglobin ≥8g/dL, ANC ≥1.5×10⁹/L, and no blood products, erythropoiesis-stimulating agents, or colony-stimulating factors therapy received within the past 7 days;
- Renal function: Serum creatinine is within the normal upper limit range set by the institution;
- Liver function: Total bilirubin ≤ 1.5×UNL; if total bilirubin > 1.5×UNL, then direct bilirubin should be ≤ UNL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both ≤ 2.5×UNL, albumin > 2.5 mg/dL;
Coagulation function: International normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT) ≤1.5×UNL; if the subject is undergoing anticoagulation therapy, it should be within the established therapeutic range; 9. Women of childbearing age must have a negative serum pregnancy test within 72 hours prior to the first administration of the investigational medicinal product. If the urine test result is positive or cannot be confirmed as negative, further serum pregnancy testing is required.
10. Women of childbearing age must agree to use two effective methods of birth control or undergo surgical sterilization, or choose to avoid any heterosexual intercourse throughout the study period and for 120 days after the last drug administration. (Women who have been postmenopausal for more than one year and have not undergone surgical sterilization are considered infertile.) Lactating women must cease breastfeeding.
11. Male subjects should agree to adopt effective contraceptive measures from the first administration until 120 days after the final administration.
Exclusion Criteria:
1. Presence of active metastases to the central nervous system or meningitis carcinomatosa.
2. There is an uncontrolled abdominal infection, intestinal obstruction, grade 3 abdominal effusion, or risk of gastrointestinal fistula and perforation.
3. Study participants received systemic immunosuppressant therapy within 28 days prior to treatment.
4. Known to be allergic to any investigational product or any excipient of the investigational product.
5. Diagnosed with other malignancies within the past 5 years, and the tumor is currently in a progressive stage or requires therapy (excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical carcinoma in situ that has undergone potential radical treatment).
6. There is active autoimmune disease, and systemic therapy (including the use of disease-modifying drugs, corticosteroids, or immunosuppressants) has been received in the past two years. Replacement therapy (e.g., thyroxine replacement for hypothyroidism, insulin therapy for diabetes, or physiological glucocorticoid supplementation for adrenal/pituitary insufficiency) is not considered systemic therapy.
7. Previously suffered from (non-infectious) pneumonia requiring glucocorticoid therapy, or currently suffering from pneumonia.
8. There is an active infection requiring systemic therapy. 9. The presence of any history of disease, therapy, or laboratory abnormalities that could potentially interfere with the test results, affect the subject's full participation, or be deemed unsuitable for the subject's participation in the study by the Sub investigator.
10. Past or current presence of mental disease or drug abuse, deemed by the sub investigator as unable to comply with trial requirements.
11. Already pregnant or in lactation, or plans to become pregnant or cause pregnancy during the trial period (from the start of pre-screening or screening visit to 120 days after the final administration).
12. Known infection with Human Immunodeficiency Virus (HIV1/2 antibody positive).
13. Known to have hepatitis B (e.g., HBV Hepatitis B Surface Antigen positive) or hepatitis C (e.g., HCV RNA test positive).
14. Received any live vaccine within 30 days prior to the first use of the investigational medicinal product.
研究計画
研究はどのように設計されていますか?
デザインの詳細
- 主な目的:処理
- 割り当て:なし
- 介入モデル:単一グループの割り当て
- マスキング:なし(オープンラベル)
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的:Experimental Group
low-dose radiotherapy (LDR) sequentially combined with serplulimab, bevacizumab analog, and irinotecan or albumin-bound paclitaxel group
|
low-dose radiotherapy (LDR) sequentially combined with serplulimab, bevacizumab analog, and irinotecan or albumin-bound paclitaxel
|
この研究は何を測定していますか?
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
PFS
時間枠:12ヶ月
|
無増悪生存期間
|
12ヶ月
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
OS
時間枠:36ヶ月
|
全生存
|
36ヶ月
|
|
ORR
時間枠:12ヶ月
|
客観的な回答率
|
12ヶ月
|
|
DCR
時間枠:12ヶ月
|
疾患制御率
|
12ヶ月
|
|
DOR
時間枠:36 months
|
Duration of remission
|
36 months
|
|
Safety assessment
時間枠:36 months
|
TEAEs
|
36 months
|
協力者と研究者
スポンサー
捜査官
- スタディチェア:Qi Xu, Master、Zhejiang Cancer Hospital
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- R-ICP
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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