This is a single-arm, single-center, exploratory clinical study. A total of 20 participants with metastatic pancreatic ductal adenocarcinoma (with liver or lung metastasis) who have experienced disease progression after or are intolerant to standard first-line chemotherapy (based on the AG regimen \[Albumin-bound Paclitaxel plus Gemcitabine\]) will be enrolled.The study aims to evaluate the safety, efficacy, and underlying immunological mechanisms of Multimodal Thermal Therapy (MTT) combined with a KRAS G12V mRNA vaccine, S-1, and Sintilimab.
Aged ≥ 18 years old with no restriction on gender.
Patients with advanced pancreatic cancer or postoperative recurrent pancreatic cancer confirmed by histopathological or cytological examination.
Tumor tissues are confirmed to carry KRAS G12V mutation via sequencing and bioinformatics analysis (valid test reports obtained within the previous 12 months and recognized by the investigator are acceptable). In the dose expansion phase, patients must harbor at least one HLA allele capable of effectively presenting the corresponding antigen, including HLA-A11:01, HLA-A03:01, HLA-A30:01, HLA-A68:01, HLA-C01:02, HLA-C03:03, and HLA-C03:04.
Disease resistance or intolerance to prior AG-based chemotherapy regimens.
Presence of diffuse hepatic or pulmonary metastases.
Prior local treatment including radiofrequency ablation, microwave ablation, radiotherapy or other local therapies for metastatic lesions.
Current participation in other interventional clinical studies and receiving investigational treatment.
Diagnosis of any other malignant disease within 5 years prior to the first study drug administration (excluding radically treated basal cell carcinoma, squamous cell carcinoma of the skin, and/or radically resected in situ carcinoma).
Single group
Multimodal Thermal Therapy (MTT) System
DeviceThe MTT system is a medical device that performs sequential ablation therapy. Treatment consists of initial cryoablation followed immediately by radiofrequency ablation (RFA) to achieve a synergistic thermal effect against the tumor.
KRAS G12V mRNA Vaccine
Biological/VaccineAdministered via intramuscular injection at a dose of 1 mg. The first dose will be given 1 to 3 days after Multimodal Thermal Therapy (MTT). Subsequent doses will be administered every 3 weeks (Q3W) according to the study dosing schedule and clinical discretion.
Sintilimab
DrugAdministered via intravenous infusion at a dose of 200 mg on Day 1 (d1). Treatment will begin on 7 days after MTT and will be repeated every 3 weeks (Q3W) until disease progression or unacceptable toxicity.
S-1
DrugOnly participants aged \<80 years will receive oral S-1. Treatment starts on Day 7 after MTT at a dose of 40-60 mg twice daily (bid) on Days 1 to 14 (d1-14) of each cycle. Cycles are repeated every 3 weeks (Q3W) until disease progression or unacceptable toxicity.
Incidence and Severity of Adverse Events (CTCAE v6.0)
To assess the safety profile of the combination regimen (MTT + KRAS G12V mRNA vaccine + Sintilimab ± S-1) in patients with metastatic pancreatic cancer. Safety will be evaluated by recording the incidence, type, and maximum grade of adverse events (AEs) and serious adverse events (SAEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.
Frequency of Dose Modifications and Treatment Discontinuations
To evaluate patient tolerability to the multimodal regimen. Tolerability is defined as the ability of participants to receive the full planned treatment. Specifically, it measures the proportion of participants requiring dose modifications, treatment delays, treatment interruptions, or permanent discontinuation of any component of the therapy (MTT, S-1 \[for those \<80 years\], Sintilimab, or mRNA vaccine) due to adverse events.
Progression-Free Survival (RECIST 1.1)
Time from the date of first study intervention to the date of radiographic disease progression per RECIST version 1.1, death from any cause, or the date of the last effective follow-up. Radiographic assessments will be performed every 1-2 months using contrast-enhanced abdominal MRI or CT imaging.
Overall Survival
Time from the date of first study intervention to the date of death from any cause or the date of the last confirmed survival follow-up. Long-term survival will be tracked through regular follow-up visits until death, loss to follow-up, or study termination.
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