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.
⁃ Participants must meet all of the following criteria to be eligible for this study:
• Age ≥18 years and ≤75 years, regardless of gender.
• Histologically or cytologically confirmed pancreatic ductal adenocarcinoma.
• Radiologically confirmed locally advanced disease, defined as:
∙ No distant metastasis.
‣ Pancreatic head/uncinate process tumors: Tumor contact with the superior mesenteric artery (SMA) \>180°.
‣ 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.
‣ 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.
• KRAS G12D mutation confirmed by tissue histology or peripheral blood testing.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• No prior antitumor therapy (including radiotherapy, chemotherapy, targeted therapy, or immunotherapy).
• At least one radiologically measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• If biliary obstruction is present, it must have been relieved prior to study entry, and the expected survival time is \>3 months.
• Signed written informed consent obtained before performing any study-related procedures.
⁃ 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:
• Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L.
∙ White blood cell (WBC) count ≥3.0 × 10\^9/L.
∙ Platelets ≥100 × 10\^9/L.
∙ Hemoglobin \>9 g/dL.
∙ Albumin ≥3.0 g/dL.
∙ Total bilirubin ≤1.5 × upper limit of normal (ULN).
∙ Prothrombin time and activated partial thromboplastin time ≤1.5 × ULN.
∙ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
∙ Serum creatinine ≤1.5 × ULN or creatinine clearance (calculated using Cockcroft-Gault formula) ≥50 mL/min.
• Electrocardiogram: QTcF interval ≤450 msec for males and ≤470 msec for females.
⁃ 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 participants with partners of childbearing potential must agree to use effective contraception from the time of signing the informed consent form until 180 days after the last dose of the study drug (whichever is later). A female is considered not of childbearing potential if postmenopausal for at least 1 year, or surgically sterilized (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).