Liposomal Irinotecan, 5-fluorouracil/Calcium Folinate, Oxaliplatin, and Adebrelimab in Combination With Radiotherapy for Resectable or Borderline Resectable Pancreatic Cancer With Risk Factors：A Prospective Exploratory Study

Summary

Pancreatic cancer is a highly malignant digestive system tumor with a very poor prognosis. In recent years, both the incidence and mortality rates of pancreatic cancer have shown a marked upward trend worldwide. Global cancer statistics from 2020 indicate that approximately 495,000 new cases of pancreatic cancer are diagnosed annually, with about 466,000 deaths attributed to this disease each year. Based on the anatomical relationship between the tumor and blood vessels, pancreatic cancer is classified into three types: resectable, borderline resectable, and unresectable. The onset of pancreatic cancer is often insidious, with approximately 80% of patients presenting with advanced disease at the time of initial diagnosis, thereby losing the opportunity for radical surgical resection. Only 15-20% of patients are eligible for radical surgery at the time of initial diagnosis. However, even after surgical resection, many patients still experience early recurrence, leading to a very poor prognosis. This highlights the significant limitations of relying solely on surgery for disease control. Currently, there is no standard neoadjuvant treatment protocol for pancreatic cancer. Recent neoadjuvant clinical trials have primarily referenced chemotherapy regimens used for advanced pancreatic cancer, which may include chemotherapy and/or radiotherapy. Recommended chemotherapy regimens include the FOLFIRINOX regimen, gemcitabine plus nab-paclitaxel, gemcitabine plus cisplatin (for BRCA1/2 mutations), and gemcitabine plus S-1. At the 2023 ASCO Annual Meeting, updated data from the NAPOLI-3 study showed that the NALIRIFOX regimen (irinotecan liposome, oxaliplatin, 5-fluorouracil, and leucovorin) achieved overall survival (OS) endpoints in first-line treatment of metastatic pancreatic cancer patients compared to the AG regimen, with clinical significance. Based on this study, the NCCN guidelines have included the NALIRIFOX regimen as a recommended first-line treatment for advanced pancreatic cancer. Given the therapeutic and safety advantages of irinotecan liposome over irinotecan in pancreatic cancer, this study aims to further explore the efficacy and safety of irinotecan liposome, 5-fluorouracil/leucovorin, oxaliplatin, and adabelimab combined with radiotherapy for resectable or borderline resectable pancreatic cancer with high-risk factors. The goal is to identify a more effective treatment option for patients with borderline resectable pancreatic cancer (BRPC) and resectable pancreatic cancer (RPC), thereby improving survival outcomes. This study is a prospective, single-arm, exploratory trial designed to evaluate the efficacy and safety of irinotecan liposome, 5-fluorouracil/leucovorin, oxaliplatin, and adabelimab combined with radiotherapy for resectable or borderline resectable pancreatic cancer with high-risk factors, with a planned enrollment of 37 patients. After screening and meeting the inclusion and exclusion criteria, eligible patients will provide informed consent and undergo neoadjuvant treatment with irinotecan liposome, 5-fluorouracil/leucovorin, oxaliplatin, and adabelimab (with a 2-week cycle) for a total of four cycles of preoperative chemotherapy combined with immunotherapy, along with five sessions of short-course radiotherapy.

Eligibility

Inclusion Criteria:

Patients must meet the following criteria to be eligible for enrollment in this study:

1. Age 18 to 75 years, regardless of gender;
2. Histologically or cytologically confirmed pancreatic cancer (arising from the pancreatic ductal epithelium), as assessed by a multidisciplinary team (MDT), with clinical records indicating resectable or borderline resectable pancreatic cancer with high-risk factors. (According to the 2022 edition of the CSCO guidelines, borderline resectable pancreatic cancer is defined as: ① Tumor contact with the portal vein-superior mesenteric vein \> 180°, or contact ≤180° combined with irregular venous contour or venous thrombosis, but with the possibility of complete resection and safe reconstruction; tumor contact with the inferior vena cava; ② (For pancreatic head/uncinate process tumors) Tumor contact with the common hepatic artery, but without involvement of the celiac artery or the origin of the left or right hepatic arteries, with the possibility of complete resection and safe reconstruction; tumor contact with the superior mesenteric artery ≤180°; tumor contact with variant arteries (e.g., accessory right hepatic artery, replaced right hepatic artery, replaced common hepatic artery, etc.). (For pancreatic body/tail tumors) Tumor contact with the superior mesenteric artery ≤180°; tumor contact with the celiac artery ≤180°.) (According to the 2022 edition of the CSCO guidelines, high-risk factors are defined as "very high CA19-9, large primary tumor, massive regional lymph node metastasis, significant weight loss, and severe pain." In this study, high-risk factors are defined as "CA199 \> 200 U/mL, maximum tumor diameter \> 2 cm, N1 or higher.")
3. Presence of at least one measurable lesion as a target lesion (according to RECIST v1.1 criteria);
4. No prior anti-tumor treatment (including radiotherapy, ablation, chemotherapy, targeted therapy, immunotherapy, etc.) or investigational drug therapy;
5. ECOG performance status: 0-1;
6. Life expectancy of ≥ 3 months;
7. Adequate function of major organs, defined as meeting the following criteria (without transfusion of blood products or administration of hematopoietic growth factors within 14 days prior to randomization):

(1) Absolute neutrophil count ≥ 1.5 × 10⁹/L; platelets ≥ 80 × 10⁹/L; hemoglobin ≥ 9 g/dL; serum albumin ≥ 3 g/dL; (2) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (biliary drainage is permitted for biliary obstruction); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (for patients with liver metastasis, up to ≤ 5 × ULN is allowed); (3) Serum creatinine ≤ 1.5 × ULN, and creatinine clearance ≥ 60 mL/min; (4) International Normalized Ratio (INR) ≤ 1.5 × ULN and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (patients on stable doses of anticoagulation therapy, such as low molecular weight heparin or warfarin, with INR within the therapeutic range of the anticoagulant, are eligible for screening); (5) Electrocardiogram: QTcF ≤ 450 ms (male), ≤ 470 ms (female); (6) Echocardiogram: Left ventricular ejection fraction (LVEF) ≥ 50%; 8. Women of childbearing potential must have a negative serum pregnancy test within 3 days prior to randomization and agree to use an appropriate method of contraception during the study and for 6 months after the end of treatment. For men, they should be surgically sterile or agree to use an appropriate method of contraception during the study and for 3 months after the end of treatment; 9. The subject voluntarily agrees to participate in this study and provides written informed consent.

Exclusion Criteria:

Patients with any of the following criteria are ineligible for enrollment in this study:

1. Pancreatic cancer originating from non-ductal epithelium of the pancreas, including pancreatic neuroendocrine tumors, pancreatic acinar cell carcinoma, pancreatoblastoma, and solid-pseudopapillary neoplasms;
2. Patients with known central nervous system metastasis;
3. Severe gastrointestinal dysfunction (e.g., bleeding, obstruction; inflammation greater than Grade 2; diarrhea greater than Grade 1);
4. Presence of third-space effusions (other than ascites) that cannot reach a stable state within 2 weeks prior to randomization (e.g., large pleural effusion that requires intervention after removal of drainage);
5. Clinically symptomatic ascites requiring paracentesis or drainage, or patients who have undergone ascites drainage within the past 3 months (exceptions include those with minimal ascites detectable only on imaging and controllable without clinical symptoms);
6. Known interstitial lung disease, excluding interstitial changes detected only on imaging;
7. Known peripheral neuropathy (CTCAE ≥ Grade 3);
8. Known deficiency or low activity of dihydropyrimidine dehydrogenase;
9. Severe infection within 4 weeks prior to enrollment (CTCAE \> Grade 2), such as severe pneumonia requiring hospitalization, bacteremia, or infectious complications; presence of signs and symptoms of infection within 2 weeks prior to randomization that require intravenous antibiotic therapy (excluding prophylactic use of antibiotics);
10. Receipt of any of the following treatments:

    * Use of strong inhibitors/inducers of CYP3A4, CYP2C8, or strong inhibitors of UGT1A1 within 2 weeks prior to enrollment;
    * Radiotherapy within 2 weeks prior to enrollment;
    * Major surgery (e.g., thoracotomy, laparotomy) within 4 weeks prior to enrollment;
    * Other investigational drug therapy within 4 weeks prior to enrollment, unless it was an observational (non-interventional) clinical study or follow-up of an interventional clinical study;
11. Abnormal coagulation function, tendency to bleed, or ongoing thrombolytic or anticoagulant therapy. Low-dose aspirin (≤100 mg/day) and low molecular weight heparin (e.g., enoxaparin 40 mg/day or equivalent doses of other low molecular weight heparins) for prophylactic use are permitted;
12. Uncontrolled cardiac clinical symptoms or diseases, such as: (1) NYHA Class 2 or higher heart failure; (2) unstable angina; (3) myocardial infarction within the past 6 months; (4) clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention;
13. History of malignancies other than pancreatic cancer within 5 years prior to enrollment, with the exception of adequately treated cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin;
14. Known hypersensitivity to irinotecan liposome, other liposomal products, oxaliplatin, 5-FU, leucovorin calcium, adadelimab, or any component of the above products;
15. Known acquired immunodeficiency syndrome (AIDS) or HIV-positive status, active syphilis infection;
16. History of definite neurological or psychiatric disorders, including epilepsy or dementia;
17. As judged by the investigator, the subject has other factors that may lead to forced discontinuation of the study, such as non-compliance with the protocol, concomitant treatment required for other severe diseases (including psychiatric diseases), clinically significant laboratory abnormalities, family or social factors that may affect the subject's safety or the collection of trial data, etc.

Conditions2

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