SEPION Study

A multicentre phase I/II study of sequential epigenetic and immune targeting in combination with nab-paclitaxel/gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC): SEPION study

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Pancreatic cancer is one of the diseases with a very high mortality rate. Previous concepts of cancer immunotherapy in patients with PDAC have often been insufficiently effective. In view of the inevitable chemoresistance in PDAC with all current treatment strategies and the non-responsiveness to current immunomodulatory approaches, new targeted strategies are clearly needed. Since both DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have been shown to stimulate immune mechanisms in tumours, both alone and especially in combination, and may sensitise them to immunomodulatory therapies, the Sepion study was designed to investigate this question in the context of first-line therapy.

The study design of the Sepion study was developed in collaboration with the German Medical Oncology Group (AIO), one of the largest scientific working groups within the German Cancer Society (Deutsche Krebsgesellschaft e. V.).

The Phase 1/2 SEPION study (NCT04257448) is evaluating the safety and tolerability of the DNMTi azacitidine and the HDACi romidepsin as single agents or combination therapy, each in combination with nab-paclitaxel and gemcitabine (standard therapy), and in another part of the study, the potential of tumour-directed immune defence with durvalumab and lenalidomide as consolidation therapy is being evaluated.
In order to accommodate the different therapeutic approaches, the study consisted of three parts. The dose escalation phase (part 1a) was followed by the dose expansion and consolidation phase (part 1b), and the study therapy was completed with a third, subsequent consolidation immune targeting phase (part 2).

In study part 1a, a standard 3+3 design for dose escalation, the highest tolerated dose was determined for romidepsin (arm A), azacitidine (arm B) and both active substances (arm C) in combination with nab-paclitaxel and gemcitabine. Here, the study treatment was administered in the respective arms until intolerance for a maximum of 3 cycles in a total of 19 enrolled patients, while in a standard arm (N=23) only nab-paclitaxel/gemcitabine was administered. After 3 patients had been treated in each of the treatment arms A, B and C, all safety data were evaluated by the Data Safety Monitoring Board.

For the dose expansion planned in the second part of the study (1b), the recommended dose (RDE) and the recommended treatment arm (romidepsin (arm A) or azacitidine (arm B) or a combination of both (arm C)) recommended in the dose-finding part (1a) continued with additional patients to be included over 3 treatment cycles until 75 patients are enrolled in the study. Those patients who continue to show stable or improved disease progression after 3 treatment cycles will be enrolled in study part 2, the immune-modulating consolidation therapy. In this consolidation phase, all patients will receive combination therapy with durvalumab and lenalidomide for a maximum of 12 months.

A total of 85 patients were screened between May 2020 and March 2023. Of these, 73 patients received at least one dose of the study therapy. The dose escalation in Part 1a showed that arm B (azacitidine) was safely tolerated, while arms A and C were discontinued early for safety reasons. In Part 2, the immunomodulatory consolidation, 46 patients were included. Initial interim results were already presented at ESMO 2024 (https://doi.org/10.1016/j.annonc.2024.08.1588).

GWT is fully responsible for this study as the clinical sponsor. This study was financially supported by Bristol Myers Squibb and AstraZeneca. The final results of the study are expected in mid-2025.