AIRPanc: A phase 2, open-label, multicenter, randomized study evaluating neoadjuvant therapy targeting the adenosine immunosuppressive pathway in combination with immune checkpoint blockade and radiation therapy in patients with advanced pancreatic ductal adenocarcinoma who are candidates for surgical resection.
Authors: Manji Gulam Abbas , Labadie Brian William , Jamison Jacob K. , Wu Linda , Wang Shikun , Pellicciotta Ilenia , Sta Ana Sarah , Sender Naomi , Ross Isabelle , Cho Hope , Horowitz David Paul , Chabot John A. 
Published: January 2024

TPS714

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which immune checkpoint blockade (ICB) has not provided benefit, hypothesized to be due to the presence of an immunosuppressive tumor microenvironment (TME). Neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy (SBRT) may increase immunosuppression by elevating intratumoral levels of adenosine, an immunosuppressive metabolite. Adenosine, produced from adenosine triphosphate by enzymes CD39 and CD73, binds the adenosine 2a and 2b receptors (A2aR and A2bR) expressed on immune cells and inhibits critical components of the antitumor immune response. Human PDAC expresses high levels of CD73, which is strongly associated with worse progression-free survival. Preclinical investigation has demonstrated CD73 and A2aR inhibition enhances antitumor immune responses, including increasing activity of ICB. The goal of this study is to test inhibition of the adenosine immunosuppressive pathway in combination with ICB and SBRT in patients with advanced PDAC who are candidates for surgical resection after receiving neoadjuvant chemotherapy. Methods: This investigator-initiated, open-label, multicenter, phase 2 clinical trial will randomize patients with borderline resectable or locally advanced PDAC who have completed 8 cycles of neoadjuvant mFOLFIRINOX and are eligible for SBRT to one of three treatment arms: zimberelimab (anti-PD-1) alone (Arm A), zimberelimab plus quemliclustat (anti-CD73) (Arm B), or zimberelimab plus quemliclustat and etrumadenant (A2aR/A2bR inhibitor)(Arm C) for a period of 7 weeks prior to undergoing surgical resection. 40 Gy SBRT in 5 fractions, totaling a biologically effective dose (BED) of 72 Gy, will be delivered concurrently to all randomized patients starting week 2 of study treatment. Part I will comprise a six-patient safety run-in with a dose-de-escalation design in which patients will be treated according to Arm C with a plan for subsequent enrollment of 14 additional patients per arm (N=42) in Part II. The primary endpoint is CD8+ T-cell infiltration at the time of surgery compared between combination arms and Arm A. Group sample sizes of 14 achieve at least 80% power to detect an effect size of 1.23 with a significance level (alpha) of 0.05 using a two-sided two-sample t-test and adjustment for 2 comparisons. Secondary objectives include estimation of median OS, 18-month survival rate, R0 resection rate, safety profile and CA 19-9 biomarker response. Exploratory studies interrogating the tumor immune microenvironment will be performed on surgical resection specimens. The trial was opened for enrollment on May 19th, 2023. Clinical trial information: NCT06048484 .