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Purpose:Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.Patients and Methods:Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1–5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability.Results:A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.Conclusions:Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

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Background: The efficacy of immune checkpoint inhibitors is often limited by immunosuppressive tumor microenvironments (TME) and novel combination therapies are required to overcome resistance. NG-350A is a novel T-SIGn (Tumor-Specific Immuno Gene) adenoviral vector that expresses a fully human agonistic IgG anti-CD40 antibody to promote innate and adaptive immune responses. Additionally, NG-350A selectively replicates in tumor cells, allowing IV dosing to be coupled with local transgene expression in the TME, thereby targeting all tumor lesions while limiting systemic exposure. Through these immunostimulatory effects the vector is designed to re-program ‘cold’ TMEs to allow functional anti-cancer immune responses. Data from an ongoing study with IV NG-350A monotherapy have shown promising tolerability, as well as prominent and sustained elevations in inflammatory cytokines (IL-2, IFNγ, IL-17A, IL-2 and IFNα2) consistent with the mechanism of action of anti-CD40 in stimulating TME re-programming [Naing 2021]. Based on these promising initial data, we designed a study to further assess the safety, tolerability and preliminary efficacy of NG-350A + pembrolizumab. Methods: FORTIFY (NCT05165433) is an open-label, dose-escalating, phase 1a/b study of NG-350A + pembrolizumab. Eligible patients have advanced/metastatic epithelial tumors that have progressed after ≥1 line of systemic therapy and are incurable by local therapy. Patients eligible for phase 1a must have experienced failure of prior PD-1/PD-L1 inhibition as part of any prior line of therapy; patients eligible for phase 1b must have primary resistance to PD-1/PD-L1 inhibition. During phase 1a, up to 30 patients will receive escalating doses of IV NG-350A (Bayesian Optimal Interval design) to a maximum of 1 × 1012 viral particles (vp) on Day 1 and 1 × 1013 vp on Days 3 and 5 (1 cycle). Patients will receive a fixed-dose of pembrolizumab (200 mg IV) on Day 15 and then every 3 weeks thereafter for up to 35 cycles. Phase 1b will further investigate the efficacy/safety of the selected regimen in up to 3 tumor-specific cohorts using a Simon 2-stage design. Co-primary objectives are to characterize the safety and tolerability of NG-350A + pembrolizumab and to identify a recommended dose. Preliminary efficacy and immunogenicity are secondary endpoints. Pharmacodynamic outcomes will be assessed using tumor tissues and blood. Analyses of tumor tissue (serial biopsies at baseline and Day 15 of cycles 1-3 [cycles 1-2 only in Phase 1b]) will explore virus replication, transgene expression and immune/inflammatory responses. Analyses of serial blood samples will explore cytokine production and changes in peripheral immune cell subsets. Recruitment is expected to begin in Q1 2022. Citation Format: Tom Lillie, Mark O'Hara, Christian Ottensmeier, Eileen Parkes, Lee Rosen, David Krige, Marya Chaney, Jo Carter, Vladimir Evilevitch, Matthew Thomas, Aung Naing. A multicenter phase 1a/b study of NG-350A, a tumor-selective anti-CD40-antibody expressing adenoviral vector, and pembrolizumab in patients with metastatic or advanced epithelial tumors (FORTIFY) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT213.