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Background Etoposide toniribate (also known as EDO-S7.1, and previously known as CAP7.1), a novel topoisomerase II inhibitor, is activated in the presence of carboxylesterases. In specific tumor cell lines, it was found to be more active than etoposide, with in vivo activity demonstrated in several drug-resistant tumor models. Anti-tumor activity was confirmed in a Phase II randomized study in patients (pts) with relapsed BTC. Methods Pts with BTC and disease progression after ≥1 line of chemotherapy were randomized 1:1 to 3-week cycles of etoposide toniribate (200 or 150mg/m2; iv on days 1–5), or best supportive care (BSC). Pts who progressed on BSC crossed over to receive etoposide toniribate. Efficacy data collected after crossover were evaluated separately as part of this post-hoc exploratory analysis. Results The per protocol analysis set included 19 pts: 10 pts were randomized to BSC, and crossed over to etoposide toniribate after disease progression, 9 pts were randomized directly to the etoposide toniribate treatment arm. Treatment after crossover from BSC to etoposide toniribate was associated with a trend for improved disease control: n/N (%; 95% CI) 4/10 (40%; 12.2, 73.8) vs 2/10 (20%; 2.5, 55.6), with tumor control achieved in 4/10 patients (1 pt partial response, 3 pts stable disease). Risk of disease progression was 2.33 times higher during BSC treatment vs after crossover to etoposide toniribate. Crossover from BSC to etoposide toniribate was associated with a trend for prolonged median PFS (39 vs 50 days). Median OS for pooled etoposide toniribate and crossover pts was 145 (59, 243) days, estimated 1-year OS 14.1%. Median (95% CI) OS for etoposide toniribate vs crossover pts was 180 (43, 468) vs 83 (11, 243) days, HR 0.39 (0.13, 1.18), estimated 1-year OS 29.6% (5.2%, 60.7%) vs 0%. Conclusions This post-hoc analysis provides further evidence for the efficacy of etoposide toniribate and suggests that early initiation in pts with advanced BTC may offer a potential survival benefit. The efficacy of etoposide toniribate will be further investigated in a planned phase III study. Funding: CellAct Pharm GmbH and Mundipharma EDO GmbH. Clinical trial identification NCT02094560. Editorial acknowledgement Sarah Birch, PhD, at Makara Health Communications Ltd, UK, funded by Mundibiopharma Ltd. Legal entity responsible for the study CellAct Pharma GmbH. Funding CellAct Pharma GmbH, Mundipharma EDO GmbH. Disclosure U. Pape: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Shire; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen. S. Kasper: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSD; Research grant / Funding (self): Celgene; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly. J. Meiler: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sanofi/Aventis. M. Sinn: Honoraria (self): Amgen; Honoraria (self), Research grant / Funding (self): Leo Pharma; Honoraria (self), Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Incyte; Research grant / Funding (self): Merck Sharp and Dohme; Research grant / Funding (self): Servier; Research grant / Funding (self): Taiho Pharmaceutical. H. Jansen: Advisory / Consultancy: CellAct Pharma. T. Mehrling: Leadership role, Full / Part-time employment: Mundipharma EDO. K. Hilgier: Advisory / Consultancy: Mundipharma EDO. I. Wagner: Full / Part-time employment: Mundipharma EDO. N. Utku: Honoraria (self), Advisory / Consultancy, Leadership role, Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: CellAct Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma EDO; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

The first-in-class alkylating HDAC inhibitor EDO-S101 is highly synergistic with proteasome inhibition against multiple myeloma through activation of multiple pathways