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Abstract

Objective

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a dismal prognosis, largely due to late diagnosis at an unresectable stage. Neoadjuvant therapy aims to downstage tumors to achieve surgical resectability, but efficacy is limited. The immunosuppressive tumor microenvironment (TME) of PDAC renders it resistant to conventional immunotherapy. To evaluate the safety and efficacy of a novel neoadjuvant regimen (the NeoPRAG protocol) for patients with locally PDAC. The primary goal is to determine the regimen's safety in Phase I and the 1-year overall survival rate in Phase II, with the ultimate aim of improving surgical resectability and survival outcomes.

Methods

The NeoPRAG study is a prospective single-center, open-label, Phase I/II clinical trial designed to evaluate a neoadjuvant regimen in patients with locally advanced (borderline resectable or unresectable) PDAC. The treatment strategy combines the “PRaG” concept (hypofractionated Radiotherapy and Granulocyte-Macrophage Colony-Stimulating Factor [GM-CSF]) with dual checkpoint blockade and chemotherapy. The Phase I portion will determine the safety, tolerability, and recommended Phase II dose (RP2D) of the radiotherapy component using a 3 + 3 dose-escalation design. The Phase II portion will assess the preliminary efficacy of the regimen, with the primary endpoint being the 1-year overall survival (OS) rate. Secondary endpoints include objective response rate (ORR), R0 resection rate, progression-free survival (PFS), and a comprehensive panel of translational biomarkers. The study is planned to commence in December 2023. Patient enrollment and follow-up are expected to be completed by November 2026, with final data analysis scheduled for December 2026.

Conclusion

The NeoPRAG protocol outlines an innovative, multi-modal strategy that confronts the immunological barriers of pancreatic cancer. It is hypothesized that this combination will synergistically remodel the TME, induce a potent anti-tumor immune response, and ultimately improve the survival landscape for this devastating disease by increasing conversion to resectability.

Keywords

pancreatic ductal adenocarcinoma neoadjuvant therapy radiotherapy immunotherapy neoadjuvant chemotherapy

Objectives

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, with a 5-year overall survival (OS) rate of only 12% in the United States and approximately 7.2% in China.^1–3 Surgical resection is the only potentially curative treatment, yet the majority of patients are diagnosed with locally advanced (borderline resectable [BR-PDAC] or unresectable [UR-PDAC]) disease, precluding them from upfront surgery.⁴

Even among patients who undergo a complete (R0) resection, early local and systemic recurrence is common, highlighting the systemic nature of the disease from its earliest stage.^5,6

Neoadjuvant therapy has become a standard approach for BR-PDAC, with key advantages including the early eradication of micrometastases, tumor downstaging to improve the R0 resection rate, and better patient tolerance compared to postoperative adjuvant therapy.^7,8 Regimens like FOLFIRINOX and gemcitabine plus nab-paclitaxel (AG) have demonstrated the ability to convert some patients to resectability.⁹ However, overall efficacy remains insufficient, necessitating the development of more potent therapeutic strategies.

A major barrier to treatment success in PDAC is its notoriously immunosuppressive tumor microenvironment (TME). The TME is characterized by a dense desmoplastic stroma, a scarcity of effector T cells, and a high infiltration of immunosuppressive cells such as regulatory T cells (Tregs) and M2-polarized macrophages.¹⁰ This “cold” immunological landscape is a primary driver of resistance to immune checkpoint inhibitors (ICIs), which have shown minimal activity as monotherapy in this disease. Therefore, a central therapeutic goal is to transform the “cold” TME into an inflamed, “hot” environment that is responsive to immunotherapy.^11,12

Radiotherapy, particularly high-dose hypofractionated techniques like stereotactic body radiation therapy (SBRT), can induce immunogenic cell death, leading to the release of tumor-associated antigens and the generation of an in-situ vaccine effect.^13,14 This process can prime an anti-tumor immune response. Building on this, our center previously developed the “PRaG” regimen (PD-1 inhibitor, Radiotherapy, and GM-CSF), which demonstrated promising efficacy and manageable safety in patients with advanced solid tumors. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a crucial role by promoting the differentiation and activation of dendritic cells (DCs), thereby enhancing antigen presentation and amplifying the systemic immune response.^15–17

This study protocol, for the NeoPRAG trial, outlines a novel, multi-modal neoadjuvant strategy designed to overcome these barriers. The regimen combines our center's “PRaG” concept with a potent dual checkpoint inhibitor, Cadonilimab (a PD-1/CTLA-4 bispecific antibody), and standard AG chemotherapy. We hypothesize that radiotherapy will act as an in-situ vaccine, inducing immunogenic cell death, while GM-CSF enhances antigen presentation by dendritic cells. This priming of the immune system will then be unleashed by Cadonilimab, which provides a more comprehensive blockade of T-cell inhibition than single-agent ICIs. The addition of chemotherapy aims to provide direct cytotoxicity and further enhance tumor immunogenicity. We believe this synergistic combination will effectively remodel the TME, increase surgical conversion rates, and improve survival outcomes for patients with locally advanced PDAC.

Methods

Study Design

The NeoPRAG study is a prospective, single-center, open-label, Phase I/II clinical trial conducted at the Second Affiliated Hospital of Soochow University. The Phase I component utilizes a 3 + 3 dose-escalation design to establish the safety and recommended Phase II dose (RP2D) of two different hypofractionated radiotherapy schedules. The Phase II portion is a single-arm study to further evaluate the efficacy of the regimen at the determined RP2D as Figure 1.

Figure 1.

Schematic of the NeoPRAG Study Design. This Flowchart Illustrates the Treatment Protocol for the Phase I/II NeoPRAG Study in Patients with Locally Advanced Pancreatic Ductal Adenocarcinoma (PDAC). The Study Begins with a Phase I Dose-Escalation Stage Where Patients are Enrolled into One of Two Radiotherapy Cohorts: Group I Receives Two Cycles of 24Gy Delivered in 3 Fractions (8Gy*3f), and Group II Receives one Cycle of 40Gy in 5 Fractions (8Gy*5f). Following PRaG Therapy, all Patients Receive Three Cycles of Immunochemotherapy (ICI + AG). Patients are Then Evaluated for Surgical Resectability. Depending on the Outcome, They May Undergo Surgery Followed by Three Additional Cycles of ICI + AG, or Receive a Further Three Cycles of ICI + AG Before a Second Surgical Evaluation. The Regimen Determined to be Optimal in the Dose-Escalation Phase Will be Administered to Patients in the Phase II Dose-Expansion Cohort. Abbreviations: AG: nab-Paclitaxel Plus Gemcitabine; ICIs, Immune Checkpoint Inhibitors; PDAC, Pancreatic Ductal Adenocarcinoma.

Patient Eligibility Criteria

Patients must meet all inclusion criteria and none of the exclusion criteria to be enrolled.

Inclusion Criteria

Age between 18 and 75 years, inclusive.

Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC).

Locally advanced disease, defined as borderline resectable or unresectable, without distant metastases. BR-PDAC refers to pancreatic cancer with a high risk of incomplete surgical removal (a positive margin) because of the tumor's close proximity to major blood vessels. The following conditions are considered BR-PDAC: contact with the portal vein or superior mesenteric vein (SMV) of ≥180°, any contact with the inferior vena cava, and/or contact with a major artery of <180°.

ECOG performance status of 0 or 1.

At least one measurable lesion according to RECIST v1.1 criteria.

No prior radiotherapy, chemotherapy, or immunotherapy for PDAC.

Life expectancy of ≥ 3 months.

Adequate major organ function, including hematologic, hepatic, and renal function.

Ability to provide voluntary written informed consent.

Exclusion Criteria

Pregnant or breastfeeding women.

History of other malignancies within the past 5 years (except for cured non-melanoma skin cancer or cervical carcinoma in situ).

Uncontrolled central nervous system (CNS) disease or significant psychiatric disorders that would impair compliance.

Clinically significant or active cardiovascular disease.

History of immunodeficiency (including HIV), prior organ transplant requiring immunosuppressive therapy, or other autoimmune diseases requiring long-term steroid use.

Active, uncontrolled infection, including active tuberculosis.

Known hypersensitivity to any of the study drugs or their components.

Treatment Protocol

The treatment protocol is administered in four stages as Figure 2 by version 1.1:

Figure 2.

Detailed Treatment and Assessment Schedule for the NeoPRAG Study. The Figure Outlines the Detailed Timelines for Treatment Administration, Biological Sampling, and Imaging Assessments for the Study's Dose-Escalation Cohorts. Group I (Top Panel): This Cohort Receives a Single Cycle of the PRaG Regimen, Which Includes Irradiation (IR) Delivered in 3 Fractions of 8Gy Each, an Immune Checkpoint Inhibitor (ICI), and Daily GM-CSF. This is Followed by Four Cycles of AG Chemotherapy Plus ICI Before Surgical Evaluation. Group II (Middle Panel): Patients Receive a Single Cycle of the PRaG Regimen, Utilizing a Different Radiotherapy Schedule (IR; 8Gy in 5 Fractions) with Concurrent GM-CSF and Subsequent ICI. Group I, Two-Cycle Cohort (Bottom Panel): This Cohort Receives Two Complete Cycles of the PRaG Regimen (IR at 8Gy×3 Fractions per Cycle) Before Proceeding to Four Cycles of AG Chemotherapy Plus ICI. Following the Initial PRaG Phase, Patients in Both Groups Proceed to Receive up to Four Cycles of nab-Paclitaxel Plus Gemcitabine Chemotherapy (AG) Combined with ICI. After a Surgical Evaluation (Days 84–98), Patients who Undergo Resection Receive up to two Additional Cycles of Adjuvant AG Plus ICI. the Timelines Indicate key Moments for Imaging Assessments (CT/MR) and Blood Sample Collection. Abbreviations: AG: nab-Paclitaxel Plus Gemcitabine; CT/MR, Computed Tomography/Magnetic Resonance Imaging; d, day; ICIs, Immune Checkpoint Inhibitors(Cadonilimab); GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; IR, Irradiation; PDAC, Pancreatic Ductal Adenocarcinoma.

Stage 1: PRaG Therapy (Dose Escalation)

Group I: Patients receive two cycles of PRaG therapy. Each cycle includes radiotherapy (RT) at 8Gy per fraction for 3 fractions (total 24Gy) on days 4–6.

Group II: Patients receive one cycle of PRaG therapy, consisting of RT at 8Gy per fraction for 5 fractions (total 40Gy) on days 3–7.

In both groups, treatment includes concurrent GM-CSF (200μg subcutaneously daily for 7 days) and Cadonilimab (375 mg intravenously) administered within one week of completing RT.

Stage 2: Neoadjuvant Immunochemotherapy

Following Stage 1, all patients receive 3 cycles of combination therapy. Each 21-day cycle consists of Cadonilimab (375 mg IV, day 1) plus the AG regimen (nab-paclitaxel 125 mg/m² and gemcitabine 1000 mg/m² on days 1 and 8).

Stage 3: Surgical Evaluation and Treatment

After completing Stage 2, patients are evaluated for surgical resectability by a multidisciplinary team. Patients deemed resectable will undergo radical surgery. Those who remain unresectable will proceed to Stage 4.

Stage 4: Adjuvant/Continued Immunochemotherapy

Patients who underwent surgery and those who remain unresectable will receive an additional 3 cycles of Cadonilimab plus the AG regimen.

The planned duration for the study is approximately 3 years. Patient enrollment and follow-up will be completed from December 22, 2023 to December 21, 2026. Data management, analysis, study summarization, and manuscript publication are planned for December 2026.

Study Endpoints

Phase I Primary Endpoint: To evaluate safety and tolerability, defined by the incidence of dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs), graded according to CTCAE v5.0.

Phase II Primary Endpoint: To determine the 1-year overall survival (OS) rate.

Secondary Endpoints: To assess objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1; progression-free survival (PFS) and median OS; the rate of conversion to surgery and the R0 resection rate; and pathological response.

Exploratory Endpoints: To analyze changes in peripheral T-lymphocyte subsets, serum cytokine levels, and the tumor immune microenvironment, including T-cell receptor (TCR) repertoire analysis via single-cell sequencing on serial blood and tissue samples.

Statistical Analysis

The Phase I portion will follow a 3 + 3 dose-escalation design. The sample size for Phase II was calculated to detect an improvement in the 1-year OS rate from 40% (historical control) to an anticipated 60% (α=0.05, 80% power), requiring 36 patients. Accounting for a 10% dropout rate, 40 patients will be enrolled in Phase II. Survival outcomes (PFS and OS) will be analyzed using the Kaplan-Meier method, and Cox proportional hazards regression will be used for multivariate analysis. All statistical analyses will be performed using SPSS v25.0 or an equivalent software package.

Ethics and Dissemination

This study protocol was approved by the Ethics Committee of The Second Affiliated Hospital of Soochow University (Address: No. 1055 Sanxiang Road, Suzhou, China), with approval number JD-LK2023100-IR01, on December 22, 2023. and will be conducted in accordance with the Declaration of Helsinki. The study is registered in ClinicalTrails. gov (NCT06345599). The results of this study will be disseminated through presentations at scientific conferences and publication in a peer-reviewed journal.

Consent to Participate

All patients will provide written informed consent before enrollment. It is mandatory for this consent document to be executed with the signatures of both the study participant and the investigator-delegated research professional responsible for the consent process. The acquisition of consent at each respective site shall be conducted by the study investigator or coordinator. The consent explicitly provides for the collection and utilization of participant data and biological specimens, and its execution shall be documented within the medical record.

Discussion

The NeoPRAG study protocol presents a rationally designed, multi-pronged neoadjuvant strategy for locally advanced PDAC, a disease with few effective treatment options. The core of this trial is the hypothesis that synergistically combining local ablative therapy, dual-target immunotherapy, and systemic chemotherapy can overcome the profound immunosuppression of the PDAC TME.

A central, innovative component of this regimen is the “PRaG” concept,¹⁷ which leverages hypofractionated radiotherapy as an in-situ vaccine to initiate an anti-tumor immune response. The inclusion of GM-CSF is critical, as it aims to enhance the recruitment and activation of antigen-presenting cells (APCs), thereby amplifying the vaccine effect and promoting a robust, systemic T-cell response. To fully capitalize on this primed state, we employ Cadonilimab, a PD-1/CTLA-4 bispecific antibody, to deliver a more comprehensive blockade of T-cell inhibitory signals than single-agent ICIs,¹⁸ which have historically failed in this “cold” tumor setting. Finally, the standard AG chemotherapy backbone serves a dual role by providing direct tumor cytotoxicity while also potentially increasing tumor immunogenicity.^19,20

Managing potential toxicities is a critical aspect of this trial design. The combination of radiotherapy, dual immunotherapy, and chemotherapy carries a risk of overlapping and cumulative adverse events. Therefore, the protocol includes stringent guidelines for toxicity monitoring, grading, and management, including pre-defined dose adjustment rules to ensure patient safety. Another challenge in this setting is the accurate radiographic assessment of treatment response, as post-treatment inflammation and fibrosis can obscure true tumor shrinkage.¹³^21–23 To address this, our protocol incorporates a multi-modal evaluation strategy combining advanced imaging techniques (CT, MRI, PET-CT) with serial biomarker analysis (eg, CA19-9), though the definitive measures of efficacy will be the surgical conversion rate, R0 resection rate, and pathological response. To further explore the biological impact of the NeoPRAG regimen, collected tumor specimens will undergo comprehensive analysis. Pathological response will be assessed using standardized tumor regression grading systems. Furthermore, exploratory biomarker studies will be conducted on tissue and blood samples. These analyses will include molecular profiling and multiplex immunohistochemistry to characterize the tumor microenvironment, specifically investigating changes in the infiltration and activation status of immune cell populations such as lymphocytes and macrophages, as well as the activity of cancer-associated fibroblasts.

A major strength of this study is its comprehensive translational research component. By collecting and analyzing serial biological samples, we aim to deeply investigate the immunological mechanisms of the NeoPRAG regimen. This work has the potential to identify biomarkers that can predict which patients are most likely to benefit from this approach, paving the way for personalized immunotherapy strategies in the future.^24–26

The reporting of this study protocol conforms to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 guidelines.²⁷

Conclusion

In conclusion, the NeoPRAG study protocol outlines a rationally designed and ambitious neoadjuvant strategy that directly confronts the immunological hurdles of pancreatic cancer. If successful, this trial could establish a novel, effective treatment paradigm for patients with locally advanced PDAC, increasing their eligibility for curative-intent surgery and meaningfully improving survival in this devastating disease.

Footnotes

Abbreviations

Acknowledgments

The authors thank the patients and their families as well as the investigators. The conception and design of the NeoPRAG study were developed by the research team. The principal investigator is responsible for the overall project leadership and supervision. Investigators within the Department of Hepatobiliary Surgery and Oncology Center are responsible for patient recruitment,treatment implementation,data collection,and patient follow-up. Medical monitoring,clinical data management,and statistical analysis support are provided by the relevant departments and personnel involved in the study design. All authors were involved in drafting the manuscript and critically revising it for important intellectual content. All authors approved the final version of the manuscript for submission.

ORCID iD

Liyuan Zhang

Ethics and Dissemination

This study was approved by the Institutional Review Board of the Second Affiliated Hospital of Soochow University (Approval No. JD-LK-2023-100-I01) and will be conducted in accordance with the Declaration of Helsinki. The study is registered in ClinicalTrails. gov (NCT06345599). All patients will provide written informed consent before enrollment. The results of this study will be disseminated through presentations at scientific conferences and publication in a peer-reviewed journal.

Funding

This work was supported by the National Natural Science Foundation of China (82102824),Suzhou Gusu Health Talent Program (GSWS2022028),Open Project of State Key Laboratory of Radiation Medicine and Protection of Soochow University(GZN1202302),New medical technology project of the Second Affiliated Hospital of Soochow University(23zl001),Multi-center Clinical Research Project for Major Diseases in Suzhou(DZXYJ202304),Suzhou Applied Basic Research (Medical and Health) Science and Technology Innovation Project (SYW2024095) and The Scientific Research Program for Young Talents of China National Nuclear Corporation. Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX24_1814). Gusu Talent Program (GSWS2022053). Open project of the State Key Laboratory of Radiology and Radiation Protection of Soochow University (GZK1204048).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

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A Phase I/II Study Protocol of a Novel Neoadjuvant ‘PRaG’ Regimen (Radiotherapy,GM-CSF,and Cadonilimab) with AG Chemotherapy to Improve Resectability in Locally Advanced Pancreatic Ductal Adenocarcinoma: The NeoPRAG Study

Abstract

Objective

Methods

Conclusion

Keywords

Objectives

Methods

Study Design

Patient Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Treatment Protocol

Stage 1: PRaG Therapy (Dose Escalation)

Stage 2: Neoadjuvant Immunochemotherapy

Stage 3: Surgical Evaluation and Treatment

Stage 4: Adjuvant/Continued Immunochemotherapy

Study Endpoints

Statistical Analysis

Ethics and Dissemination

Consent to Participate

Discussion

Conclusion

Footnotes

Abbreviations

Acknowledgments

ORCID iD

Ethics and Dissemination

Funding

Declaration of Conflicting Interests

References