Surufatinib Plus mFOLFIRINOX and PD-1 Inhibitor as the Neoadjuvant Therapy for High-risk or Borderline Resectable Pancreatic Cancer

Neoadjuvant Therapy With Surufatinib Combined With mFOLFIRINOX and Toripalimab for High-risk or Borderline Resectable Pancreatic Cancer: A Phase II, Single-arm, Single-center Study

The goal of this clinical trial is to learn if surufatinib (VEGFR-TKI) plus toripalimab (PD-1 inhibitor) and mFOLFIRINOX (chemotherapy) works as neoadjuvant therapy for patients with high-risk or borderline resectable pancreatic cancer. It will also learn about the safety of the combination regimen. The main questions it aims to answer are:

Does the treatment regimen of surufatinib combined with immunotherapy and chemotherapy could provide further survival benefits for patients with high-risk resectable or borderline resectable pancreatic cancer as neoadjuvant therapy?

Is the safety of this combination therapy tolerable?

Participants will:

Take surufatinib (200mg, qd, po, q2w), Toripalimab (3mg/kg, iv, d1, q2w), Oxaliplatin (68 mg/m², iv, d1, q2w), Irinotecan (135 mg/m², iv, d1, q2w), Calcium folinate (400 mg/m², iv, d1, q2w), 5-FU (2400 mg/m², iv). Treatment for up to 8 cycles.

Visit the clinic once every 8 weeks (± 7 days) for checkups and tests. Keep a diary of their symptoms and record daily medication doses.

This study is a single-center, single-arm, phase II study.

Preoperative neoadjuvant treatment plan:

• Surufatinib: 200 mg orally once daily, continuous dosing, with a 14-day treatment cycle;
• Toripalimab: 3 mg/kg per dose, intravenous infusion over 1 hour on day 1, every 14 days per treatment cycle;
• Oxaliplatin: 68 mg/m² intravenous infusion over 2 hours on day 1;
• Irinotecan: 135 mg/m² intravenous infusion over 30-90+ minutes on day 1;
• Calcium folinate: 400 mg/m² intravenous infusion over 2 hours on day 1;
• 5-FU: 2400 mg/m² continuous intravenous infusion over 46 hours; repeated every 14 days per treatment cycle.

Neoadjuvant treatment will be administered for up to 8 cycles. During treatment, tumor assessments using imaging will be conducted every 8 weeks (±7 days). For patients achieving stable disease, partial response, or complete response, it will be evaluated whether surgery is feasible. Surgery should occur at least 2 weeks after the last neoadjuvant treatment.

Postoperative adjuvant treatment plan:

• Adjuvant treatment will begin within 4-8 weeks after surgery, with the specific regimen determined by the investigator.
• During postoperative adjuvant treatment, tumor assessments using imaging will be conducted every 8 weeks (±7 days) until disease progression (RECIST 1.1) or death (during patient treatment), or until intolerable toxicity occurs. Subsequent treatment after disease progression and survival status will also be recorded.

Inclusion Criteria:

1. Voluntarily sign the informed consent form.

2. Ages 18-75 years, no gender restrictions.

3. Patients with high-risk resectable or borderline resectable pancreatic cancer confirmed by pathological tissue or cytology:

   • High-risk features include: ① Imaging findings; ② Significant elevation of CA 19-9 (baseline >210 U/ml, Vincent P Groot, Ann Surg. 2019 Jun;269(6):1154-1162); ③ Large primary tumor (>3 cm, Vincent P Groot, Ann Surg. 2019 Jun;269(6):1154-1162); ④ Large regional lymph nodes (it is recommended to use imaging to assess lymph node metastasis, or if the number of metastatic lymph nodes >3, N2 stage); ⑤ Excessive weight loss (more than 5 kg within 1 month); ⑥ Severe pain (main complaint of abdominal pain is sufficient).
   • Definition of borderline resectable: ① Arteries: Tumor contact with the celiac trunk (≤180°) or superior mesenteric artery (SMA) (≤180°), or involvement of the hepatic artery that is reconstructable. ② Veins: Narrowing or occlusion of the superior mesenteric vein (SMV)/portal vein (PV), but the proximal/distal vessels are suitable for reconstruction.

4. The patient must have at least one measurable lesion (RECIST 1.1).

5. No BRCA1/2 or PALB2 mutations.

6. Has not previously received systemic therapy or local radiotherapy.

7. ECOG performance status 0-1;

8. Expected survival ≥24 weeks;

9. No surgical contraindications;

10. Blood tests (without transfusion in the past 14 days) 1) Absolute neutrophil count ≥1.5×10⁹/L, platelets ≥100×10⁹/L, hemoglobin concentration ≥9 g/dL; 2) Liver function tests (AST and ALT ≤2.5×ULN, total bilirubin ≤1.5×ULN; if there are liver metastases, AST and ALT ≤5×ULN); 3) Kidney function (serum creatinine ≤1.5×ULN, creatinine clearance (CCr) ≥60 ml/min); 4) Coagulation, international normalized ratio (INR) ≤1.5×ULN, prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤1.5×ULN;

11. Male or female patients of reproductive potential voluntarily use effective contraception during the study period and for 6 months after the last study treatment, such as dual-barrier contraceptive methods, condoms, oral or injectable contraceptives, intrauterine devices, etc. All female patients will be considered of reproductive potential unless the female patient is naturally menopausal, has undergone induced menopause, or has had sterilization procedures (such as hysterectomy, bilateral salpingo-oophorectomy, or ovarian irradiation).

Exclusion Criteria:

1. Patients with distal metastasis;
2. Received blood transfusion therapy, blood products and hematopoietic factors such as albumin and granulocyte colony-stimulating factor (G-CSF) within 14 days before enrollment;
3. Received any surgical or invasive treatment or operation within 4 weeks prior to enrollment (except for intravenous catheterization, puncture and drainage, etc.);
4. Known allergy to any drug in the study;
5. Presence of hypertension that cannot be controlled by medication, as prescribed as: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg;
6. The patient currently has any disease or condition that affects the absorption of the drug, or the patient has difficulty swallowing and cannot take surufatinib orally;
7. Patients currently have active gastric and duodenal ulcers, ulcerative colitis and other gastrointestinal diseases or active bleeding from unresected tumors, or other conditions that may cause gastrointestinal bleeding or perforation as determined by the investigator;
8. Uncontrollable malignant ascites (defined as ascites that cannot be controlled by diuretics or puncture methods as judged by the investigator);
9. Patients with obvious evidence or history of bleeding tendency within 3 months before enrollment (bleeding >30 mL within 3 months, with hematemesis, black feces, blood in the stool), hemoptysis (>5 mL of fresh blood within 4 weeks), or thromboembolic events (including stroke events and/or transient ischemic attack) within 10 months;
10. Clinically significant electrolyte abnormalities judged by the investigator;
11. Significant clinically significant cardiovascular disease, including but not limited to the following: acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within 6 months before enrollment; Congestive heart failure New York Heart Association (NYHA) grade >2; ventricular arrhythmias requiring medication; LVEF (left ventricular ejection fraction) < 50%;
12. Other malignant tumors within the past 5 years, except basal cell or squamous cell carcinoma of the skin after radical surgery, or carcinoma in situ of the cervix;
13. Active or uncontrolled serious infection:

1) Known human immunodeficiency virus (HIV) infection; 2) Known history of clinically significant liver disease, including viral hepatitis [for known hepatitis B virus (HBV) carriers, active HBV infection must be excluded, i.e., HBV DNA positive (>1×10^4 copies/mL or >2000 IU/mL)]; 3) Known hepatitis C virus (HCV) infection with HCV RNA positive (>1×10^3 copies/mL), or other hepatitis, cirrhosis; 14. Women who are pregnant (tested positive for pregnancy before taking the medication) or are currently breastfeeding; 15. Subjects whom the investigator considers unsuitable for participation in this clinical study due to any clinical or laboratory abnormalities or other reasons; 16. Those with routine urine test indicating urinary protein ≥2, and 24-hour urine protein quantification >1.0g;