NALIRIFOX+Adebrelimab+PULSAR for Advanced Pancreatic Cancer

Official title

A Phase I/II Clinical Trial of NALIRIFOX Combined With Adebrelimab and PULSAR as First-Line Treatment for Locally Advanced Unresectable or Metastatic Pancreatic Ductal Adenocarcinoma

Overview

This study aims to evaluate the safety and preliminary efficacy of NALIRIFOX combined with adebrelimab and PULSAR as first-line treatment for locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC). Additionally, it will explore potential predictive and efficacy-related biomarkers.

Detailed description

After confirmation of eligibility, enrolled patients will undergo radiation CT simulation and planning per standard of care. IV contrast will be administered with CT simulation at the treating physician's discretion though is not required.

Interventions

• Drug NALIRIFOX+Adebrelimab
  NALIRIFOX chemotherapy and Adebrelimab Injection
• Radiation PULSAR
  PULSAR

Primary outcome measures

• Objective response rate (RECIST v1.1) [Time frame: From the first patient enrollment until 6 months after the last patient enrollment]

Secondary outcome measures (3)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Time frame: From the first patient enrollment until 6 months after the last patient enrollment]
• Progression free survival [Time frame: From the first patient enrollment until 6 months after the last patient enrollment]
• Overall survival [Time frame: From the first patient enrollment until 6 months after the last patient enrollment]

Eligibility criteria

Inclusion criteria

• Age: 18-75 years, regardless of gender.
• Histologically confirmed pancreatic ductal adenocarcinoma (PDAC).
• Previously untreated, locally advanced unresectable or metastatic PDAC, with at least one measurable lesion (RECIST v1.1) not previously irradiated.
• ECOG Performance Status (PS): 0-1.
• Expected survival ≥ 3 months.
• Willing and able to comply with study procedures, treatment, and follow-up.
• No contraindications to radiotherapy.
• Adequate organ function: WBC ≥ 2.5×10⁹/L, ANC ≥ 1.5×10⁹/L; Platelets ≥ 75×10⁹/L; Hemoglobin (HGB) ≥ 90 g/L (no transfusion or EPO dependence within 7 days); Total bilirubin (Tbil) ≤ 1.5×ULN; ALT/AST ≤ 5×ULN;Albumin ≥ 30 g/L; INR ≤ 1.5×ULN; Serum creatinine (Cr) ≤ 1.5×ULN Urine protein ≤ 1+
• HBsAg-positive patients must have HBV-DNA ≤ 1×10³ IU/mL (copies/mL). If HBV-DNA ≥ 1×10³ IU/mL, patients may still be eligible if chronic HBV is stable and not expected to increase risk, per investigator assessment.
• Voluntary participation with signed informed consent form.

Exclusion criteria

• History of severe hypersensitivity to chimeric, human(ized) antibodies, or fusion proteins.
• Pregnant or breastfeeding women, or men/women of childbearing potential unwilling/unable to use effective contraception during the study.
• Other malignancies within 5 years, except: Malignancies treated with curative intent and no known active disease for ≥5 years with low recurrence risk; Adequately treated non-melanoma skin cancer or lentigo maligna without disease evidence; Adequately treated carcinoma in situ (e.g., cervical, breast) with no current disease.
• Symptomatic moderate/severe pleural effusion or ascites.
• Active bleeding or coagulopathy (PT >16s, APTT >43s, INR >1.5×ULN), bleeding tendency, or current use of thrombolytics/anticoagulants/antiplatelets.
• GI bleeding within 6 months or high bleeding risk (e.g., active ulcer with occult blood++). If occult blood+ persists, endoscopy required.
• High-risk esophageal/gastric varices needing intervention.
• History of drug abuse, psychiatric disorder, or inability to abstain.
• Solid organ/bone marrow transplant, or active autoimmune disease requiring systemic treatment within 2 years.
• Immunodeficiency or HIV infection.
• Objective evidence of pulmonary fibrosis, interstitial lung disease, pneumoconiosis, radiation-/drug-induced pneumonitis, or severely impaired pulmonary function.
• Major surgery within 4 weeks or minor surgery within 1 week (e.g., tooth extraction).
• Vaccination within 30 days before the first dose.
• Abdominal fistula, GI perforation, or abscess within 4 weeks.
• Any clinically significant abnormality affecting safety per investigator, including: Active infection requiring systemic therapy; Uncontrolled diabetes/hypertension (BP >140/90 mmHg despite ≤2 antihypertensives); Myocardial infarction within 6 months; Thyroid dysfunction (>NCI CTCAE v4.0 Grade 1).
• Other conditions deemed ineligible by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• West China Hospital, Sichuan University — Chengdu

Publications

• Moore C, Hsu CC, Chen WM, Chen BPC, Han C, Story M, Aguilera T, Pop LM, Hannan R, Fu YX, Saha D, Timmerman R. Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) in Preclinical Models Enhances Single-Agent Immune Checkpoint Blockade. Int J Radiat Oncol Biol Phys. 2021 Aug 1;110(5):1306-1316. doi: 10.1016/j.ijrobp.2021.03.047. Epub 2021 Mar 29. PMID 33794306
• Peng H, Moore C, Zhang Y, Saha D, Jiang S, Timmerman R. An AI-based approach for modeling the synergy between radiotherapy and immunotherapy. Sci Rep. 2024 Apr 8;14(1):8250. doi: 10.1038/s41598-024-58684-6. PMID 38589494
• Rouf S, Moore C, Saha D, Nguyen D, Bleile M, Timmerman R, Peng H, Jiang S. PULSAR Effect: Revealing potential synergies in combined radiation therapy and immunotherapy via differential equations. J Theor Biol. 2025 Jan 7;596:111974. doi: 10.1016/j.jtbi.2024.111974. Epub 2024 Oct 22. PMID 39448025
• Peng H, Moore C, Saha D, Jiang S, Timmerman R. Understanding the PULSAR effect in combined radiotherapy and immunotherapy using transformer-based attention mechanisms. Front Oncol. 2024 Dec 2;14:1497351. doi: 10.3389/fonc.2024.1497351. eCollection 2024. PMID 39687891
• Wainberg ZA, Melisi D, Macarulla T, Pazo Cid R, Chandana SR, De La Fouchardiere C, Dean A, Kiss I, Lee WJ, Goetze TO, Van Cutsem E, Paulson AS, Bekaii-Saab T, Pant S, Hubner RA, Xiao Z, Chen H, Benzaghou F, O'Reilly EM. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. La PMID 37708904
• Cho YB, Yoon N, Suh JH, Scott JG. Radio-immune response modelling for spatially fractionated radiotherapy. Phys Med Biol. 2023 Aug 7;68(16):165010. doi: 10.1088/1361-6560/ace819. PMID 37459862
• Moon EJ, Petersson K, Olcina MM. The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT. Int J Radiat Biol. 2022;98(3):439-451. doi: 10.1080/09553002.2021.1988178. Epub 2021 Nov 2. PMID 34726575
• Galluzzi L, Aryankalayil MJ, Coleman CN, Formenti SC. Emerging evidence for adapting radiotherapy to immunotherapy. Nat Rev Clin Oncol. 2023 Aug;20(8):543-557. doi: 10.1038/s41571-023-00782-x. Epub 2023 Jun 6. PMID 37280366

Identifiers

NCT: NCT07595172 · PRIM-P1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗