A Phase II Study of HRS-4642 Combined With AG (Nab-paclitaxel and Gemcitabine) as Conversion Therapy for Locally Advanced Pancreatic Cancer

This study will evaluate the effectiveness and safety of HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG regimen) as conversion therapy for patients with locally advanced pancreatic cancer. Participants will undergo regular assessments, including imaging scans and CA19-9 biomarker tests. If disease recurrence is suspected, unscheduled evaluations may be performed. For participants who discontinue treatment due to reasons other than disease progression (e.g., toxicity), tumor assessments will continue as scheduled until progression, loss to follow-up, death, consent withdrawal, or study termination. After the final treatment, participants will enter a survival follow-up phase. Investigators will contact the participants or their families approximately every month (±7 days) to collect information on survival status (date and cause of death) and any subsequent anti-cancer treatments until death, loss to follow-up, study termination, or other study endpoints are met. All follow-up information will be documented in the medical records.

Study Objectives Primary Objective: ● To evaluate the efficacy of HRS-4642 combined with AG (nab-paclitaxel and gemcitabine) as conversion therapy in patients with locally advanced pancreatic cancer, as measured by Objective Response Rate (ORR). Secondary Objectives: * To evaluate the efficacy of HRS-4642 combined with AG as conversion therapy by assessing surgical conversion rate, Disease Control Rate (DCR), CA19-9 response rate, Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and 1-year OS rate. * To evaluate the safety profile of HRS-4642 combined with AG as conversion therapy. * To assess changes in health-related quality of life from baseline using the EORTC QLQ-C30 and EORTC QLQ-PAN26 questionnaires in all participants.

Drug: HRS-4642 Injection. Investigational Product: HRS-4642 Injection. Dosage Form: Injection. Strength: 10 mL: 30 mg. Route of Administration: Intravenous Infusion. Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. Background: HRS-4642 is a highly potent, long-lasting, and selective KRAS G12D inhibitor developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Hengrui). It is a liposomal formulation. HRS-4642 specifically binds to KRAS G12D, thereby inhibiting the phosphorylation of MEK and ERK proteins, and exerts an antitumor effect.

HRS-4642 combined with AG (experimental): Dosing Regimen: * HRS-4642 was administered by intravenous infusion at 480-500 mg on Day 1 and 1200 mg on Day 8 of each 21-day cycle (Q3W, every 3 weeks). The first infusion duration should be no less than 60 minutes. If no infusion-related reaction occurs after the first dose, the duration of subsequent infusions may be appropriately shortened. * Nab-paclitaxel: 125 mg/m², intravenous infusion over 30 minutes, on Days 1 and 8, every 3 weeks. * Gemcitabine: 1000 mg/m², intravenous infusion over 30 minutes, on Days 1 and 8, every 3 weeks.

To evaluate the efficacy of HRS-4642 combined with AG (nab-paclitaxel and gemcitabine) as conversion therapy in patients with locally advanced pancreatic cancer, as measured by the Objective Response Rate (ORR).. Tumor response will be assessed by investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 via computed tomography (CT) or magnetic resonance imaging (MRI) scans. Time frame: every 6 weeks(±7 days) from the first dose of study treatment until disease progression, initiation of new anti-cancer therapy, withdrawal of consent, death, or study termination, whichever occurs first, assessed up to 24 months.

Inclusion Criteria: Participants must meet all of the following criteria to be eligible for this study: 1. Age ≥18 years and ≤75 years, regardless of gender. 2. Histologically or cytologically confirmed pancreatic ductal adenocarcinoma. 3. Radiologically confirmed locally advanced disease, defined as: 1. No distant metastasis. 2. Pancreatic head/uncinate process tumors: Tumor contact with the superior mesenteric artery (SMA) \>180°. 3. Pancreatic body/tail tumors: Tumor contact with the SMA or celiac artery \>180°; or contact with the celiac artery with aortic invasion; or tumor invasion of the jejunal branches of the SMA. 4. Inability to safely reconstruct the portal vein-superior mesenteric vein due to tumor invasion, venous occlusion, or extensive involvement of the jejunal branches of the superior mesenteric vein. 4. KRAS G12D mutation confirmed by tissue histology or peripheral blood testing. 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. 6. No prior antitumor therapy (including radiotherapy, chemotherapy, targeted therapy, or immunotherapy). 7. At least one radiologically measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 8. If biliary obstruction is present, it must have been relieved prior to study entry, and the expected survival time is \>3 months. 9. Signed written informed consent obtained before performing any study-related procedures. 10. Adequate organ function meeting the following criteria (without corrective treatment with blood components or growth factors within 14 days prior to the first dose), with test results completed within 7 days before initiation of study treatment: 1. Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L. 2. White blood cell (WBC) count ≥3.0 × 10\^9/L. 3. Platelets ≥100 × 10\^9/L. 4. Hemoglobin \>9 g/dL. 5. Albumin ≥3.0 g/dL. 6. Total bilirubin ≤1.5 × upper limit of normal (ULN). 7. Prothrombin time and activated partial thromboplastin time ≤1.5 × ULN. 8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN. 9. Serum creatinine ≤1.5 × ULN or creatinine clearance (calculated using Cockcroft-Gault formula) ≥50 mL/min. 10. Electrocardiogram: QTcF interval ≤450 msec for males and ≤470 msec for females. 11. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose and must not be lactating. Female participants of childbearing potential and male …

Enrollment: 30 participants (estimated).