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264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing administration of higher doses, reducing resistance, and permitting treatment of advanced tumors. Methods: The primary objective was to compare disease control rate (DCR) in 22 pts with unresectable BTC randomized 1:1 to 3-week cycles of EDO-S7.1 (200 or 150mg/m2; iv) given on days (d) 1–5, or best supportive care (BSC) until progression (assessed every 4 weeks). Secondary objectives were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. BSC pts could crossover to EDO-S7.1 upon progression. Results: DCR favored EDO-S7.1 (55.6% [CI 21.2, 86.3] vs BSC (20.0% [2.5, 55.6]; treatment difference –12.80, 72.39). More EDO-S7.1 treated pts achieved sustainable stable disease (SD) or partial response (PR) vs BSC. Progressive disease occurred in 40% EDO-S7.1 vs 70% BSC pts. Three pts (30%) who progressed on BSC achieved SD following crossover to EDO-S7.1, and one pt (10%) PR (total: 40.0% [12.2, 73.8]) vs two pts with SD following BSC (20.0% [2.5, 55.6]; treatment difference –0.17, 0.57; p=0.0786). Median PFS was 103d with EDO-S7.1 vs 39d with BSC (p=0.006), and median TTF 92d vs 39d, respectively (p=0.006). Median OS was 227d with EDO-S7.1 vs 162d with BSC (p=0.088), and estimated 1-year OS 44% vs 11.3%, respectively. EDO-S7.1 had significant efficacy in pts with metastatic disease (p=0.029) or without prior surgery (p=0.032). Seven pts were eligible for exploratory analysis of tumor CES via immunohistochemistry. 4/7 pts had CES+ tumors and longer median PFS (195d [163, 233]) and OS (302d [214, 838]) vs pts with CES– tumors (46d [46, 83] and 83d [43, 319], respectively). The most common drug-related adverse events (G3–4) (%) were leukopenia 65 (26.1), neutropenia 78.3 (56.5), thrombocytopenia 56.5 (17.4), anemia 52.2 (17.4), alopecia 34.4 (0), fatigue 26.1 (0), and abdominal pain 30.4 (0). Conclusions: EDO-S7.1 demonstrated efficacy in pts with advanced BTC and may provide a new biomarker-guided therapeutic option with stratification by intra-tumor CES assessment. These findings will be explored in a larger patient cohort. Clinical trial information: NCT02094560.

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.

Adiponectin (APN), a cytokine constitutively produced in fat tissue, has been shown to exert anti-inflammatory effects in various disease models. While the influence of APN on monocytic cells has been extensively studied in vitro, little is known about its role in T cells. In this study, we show that while

441 Background: Non-resectable biliary tract cancers (BTC) have poor prognosis, but are chemosensitive. CAP7.1 is a new chemical entity that releases etoposide in the presence of carboxylesterases, leading to higher intra-tumor etoposide (E) with improved safety and efficacy. Methods: The primary objective of this trial is to determine the rate of disease control (DCR) (stable disease, SD; partial response, PR and complete response, CR) according to Recist 1.1. of CAP7.1 in patients (pts) with BTC. Secondary objectives are progression free survival (PFS), overall survival (OS) and safety. Pts with adenocarcinoma arising from bile ducts or gallbladder were randomized (1:1) to either CAP7.1 or best supportive care (BSC) group (institutional palliative treatment). Pts in CAP7.1 arm subjected to a 3-week cyle (cy) with CAP7.1 on days 1-5 in 3-week cy was given with either 200 or 150mg/m2. until progression. At progression BSC pts were allowed to cross over to CAP7.1. Safety was assessed with CTCAE v 3.0 and efficacy after 2 cy of treatment. 18 /50 pts (9 in each study arm) finalized 1st stage and analyzed for efficacy and safety. Results: DCR in the CAP7.1 arm was 56%, with 5/9 of pts with SD (including tumor shrinkages), while all pts in the BSC arm progressed. The median PFS time was 3.5 months (95% CI, 1.9 to 8.4 months) in the CAP7.1 arm. 5 pts crossed over to the CAP7.1 arm. 2/3 pts continued CAP7.1 treatment up to 5 and 8 cycles as SD, respectively, while one pts achieved PR. The median OS time from first treatment with CAP7.1 was 5.9 months (95% CI, 2.6 to 15.3 months) over all evaluable pts, including BSC after crossing to CAP7.1. Commonly observed drug related adverse events (AE) are hematoxicity/myeolosuppression, various events of infection, alopecia, fatigue, nausea and abdominal pain, which were in general well managed. G3-4 neutropenia occurred in 4/10 pt at a dose of 150 mg/m²/d and in 6/11 pts at 200 mg/ m2/d; uncomplicated g 3-4 thrombocytopenia occurred in 2/11 pt at 200 and in 1/10 at 150 mg/ m2/d. Non-hematological AE were mainly mild or moderate e.g. abdominal pain and alopecia as most frequent AEs. Conclusions: CAP7.1 showed promising activity in therapy refractory advanced BTC patients.

Summary TIRC7 is a cell surface molecule which is expressed in T and B lymphocytes and negatively regulates their function. Anti-TIRC7 specific monoclonal antibody (mAb) inhibited T cell memory response to recall antigens. Up-regulation of TIRC7 on lymphocytes from joint tissue of patients with Rheumatoid Arthritis (RA) and mice with collagen induced arthritis (CIA) suggested TIRC7 as a novel target to promote anti-inflammatory reaction. Anti-TIRC7 mAb administration significantly inhibited the induction and progression of CIA and the anti-collagen IgG1 and IgG2a antibody response. Combination therapy of anti-TIRC7 mAb and soluble TNF-α receptor demonstrated an increased inhibitory effect over the single compounds on CIA. The results demonstrate the therapeutic potential of TIRC7 targeting with mAb in diseases associated with exaggerated T and B cell responses.

T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.

Increasing donor age is associated with reduced graft function. We wondered if donor age may not only affect intrinsic function but also alter the immune response of the recipient. Kidneys from young and old F-344 rats (3 vs 18 months) were transplanted into bilaterally nephrectomized young Lewis recipients and compared with age-matched controls (follow-up: 6 months). Renal function and structural changes were assessed serially in both native kidneys and allografts. Host alloreactivity, graft-infiltrating cells, and their inflammatory products were determined at intervals to examine the correlation of immune response and donor age. Functional and structural deterioration had advanced significantly in older allografts compared with age-matched native controls, whereas differences between young allografts and native controls of similar age were only minor. Changes in grafts from elderly rats were associated with a more intense host immune response early post-transplant (up to 1 month) reflected by significantly higher numbers of peripheral T and B cells, increased T-cell alloreactivity and modified cytokine patterns associated with elevated frequencies of intragraft dendritic cells, B cells, and CD31+ cells. By 6 months, recipients of young donor grafts produced comparable or more intense alloantigen-specific immune responses. Older donor grafts elicit a stronger immune response in the early period after transplantation.