Interim safety results from SEPION/AIO-PAK-0118: A multicenter, Phase I/II study of sequential epigenetic and immune targeting in combination with nabpaclitaxel/gemcitabine in patients with advanced pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains a hard-to-treat cancer entity with limited therapeutic options. We aim to enhance the anti-tumor and pro-immunogenic effect of standard-of-care nab-paclitaxel/gemcitabine (GnP) by concomitant epigenetic targeting followed by immune-modulating maintenance therapy in patients (pts) with treatment-naive metastatic PDAC. This phase 1/2, open-label, multicenter, dose-escalation/dose-expansion study evaluates the safety and tolerability of azacitidine (AZA) and romidepsin (ROM) in combination with GnP and the potential of immune-modulating consolidation with durvalumab and lenalidomide after three cycles of either GnP or GnP plus epigenetic targeting. Here we report interim results of the dose escalation. Methods: In part 1A, dose escalation of three regimen ROM/GnP (arm A), AZA/GnP (arm B) and ROM/AZA/GnP (arm C) for determination of the recommended dose for expansion (RDE) is performed with a 3 + 3 dose escalation scheme using fixed dose levels. For dose expansion (part 1B), one of the treatment arms (Arm C over B over A) is continued using a Simon two-stage design to a maximum of 35 patients. The efficacy of the sequential programmed death-ligand (PD-L)1 blockade in combination with low-dose lenalidomide is evaluated in study part 2 (consolidation part) for pts with controlled disease (DCR) after 3 cycles of part 1 therapy. Evaluation of the consolidation concept in part 2 requires a sufficient DCR based on the statistical considerations. Thus, in addition to pts in part 1A and 1B, pts treated with GnP alone are additionally recruited (standard arm), so that at least 41 pts with controlled disease after 3 cycles of therapy are available for part 2. Key eligibility includes metastatic PDAC (stage IV), ECOG 0-1 and no prior chemotherapy or radiotherapy therapy for stage IV PDAC. Primary objectives include safety and tolerability of AZA and/or ROM in combination with GnP followed by sequential immune targeting with PD-L1 blockade in combination with low-dose lenalidomide. Results: In October 2022, 76 pts were enrolled, of which 67 pts were treated with at least one dose of study medication. The median age in the treated population was 62.8 years (range: 33 - 83), 32 (47.8 %) were female, 80.6 %/13.4 % were included with ECOG 0/1. In part 1A, an RDE of 2mg/m² for ROM (N=3, dose level L-1) and 30mg/m² for AZA (N=6, dose level L1) was established, respectively. The combined administration of AZA (30 mg/m²), ROM (2 mg/m²) and GnP (arm C) led to severe DLTs, namely neutropenia, non-hematologic toxicities (> grade2) and ROM related non-hematologic toxicities (≥ grade2) in all three patients. Given the best safety profile, Arm B was chosen for the expansion part 1B. Conclusions: ROM in combination with GnP showed considerable toxicity at dose level L1 as did the combination of ROM (dose level L-1) and AZA (dose level L1) with GnP. The combination of 30 mg/m2 AZA with GnP was feasible and chosen for further expansion. Dose expansion (part 1B) and sequential immunotherapy consolidation (part 2) are ongoing. Clinical trial information: NCT04257448. Research Sponsor: GWT-TUD GmbH. Citation Format: Jens T. Siveke, Marianne Sinn, Stefan Boeck, Gabriele Siegler, Thomas Seufferlein, Joerg Trojan, Dirk Waldschmidt, Alexander Koenig, Dorothea Schipp, Ines Winkler, Sven Thorsten Liffers, Volker Kunzmann. Interim safety results from SEPION/AIO-PAK-0118: A multicenter, Phase I/II study of sequential epigenetic and immune targeting in combination with nab-paclitaxel/gemcitabine in patients with advanced pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT195.