Greten, Tim F.

Transplant oncology defines any application of transplant medicine and surgery aimed at improving cancer patients’ survival and/or quality of life. In practice, liver transplantation for selected hepato-biliary cancers is the only solid organ transplant with demonstrated efficacy in curing cancer. Four are the proposed future contributions of transplant oncology in hepato-biliary cancer (4-e). (1) evolutionary approach to cancer care that includes liver transplantation; (2) elucidation of self and non-self recognition systems, by linking tumor and transplant immunology; (3) exploration of innovative endpoints both in clinical and experimental settings taking advantage from the access to the entire liver explant; (4) extension of surgical limitation in the multidisciplinary approach to hepato-biliary oncology. The aim of this review is to define the principles of transplant oncology that may be applied to hepato-biliary cancer treatment and research, attempting to balance current evidences with future opportunities.

301 Background: Endoglin plays a critical role in angiogenesis and is implicated in resistance to VEGF inhibition. TRC105, an endoglin antibody potentiates anti-tumor activity of sorafenib (S) in preclinical HCC models. The combination of TRC105 and S demonstrated encouraging evidence of activity, including a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently, and most commonly included epistaxis, fatigue, headache and anemia. Methods: Following dose escalation, 21 pts will be enrolled at the RP2D. Four objective responses are required to reject the null hypothesis that the true response rate probability is < 5% with an alpha level of 0.1 and 80% power. Secondary endpoints: DR, PFS, frequency and severity of AEs, PK, immunogenicity, angiogenic biomarkers. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Four pts have been enrolled in phase 1b at TRC105 10 mg/kg (n=4) weekly for four doses and 15 mg/kg every other week thereafter + S 800 mg daily without DLT. One of 3 evaluable pts achieved PR (41% reduction), ongoing at month 4. Serum levels of TRC105 exceeded the target concentration following 4 weekly doses of TRC105 at 10 mg/kg (mean = 59 µg/ml, range 43-80). Mean trough concentration decreased following every other week dosing (mean = 21 µg/ml, range 17-31). Common TRC105 related AEs included ≤ G2 epistaxis and G1 headache. Common S related AEs included G3 hand foot syndrome, ≤G3 periodontal disease, G2 hypertension, ≤G2 increased lipase, ≤G2 fatigue and G1 epistaxis. Conclusions: TRC105 dosed by a hybrid schedule of 10 mg/kg weekly for four doses followed by every other week dosing at 15 mg/kg was tolerable and did not potentiate the toxicity of S. The combination of TRC105 + S demonstrated additional signs of activity, including a PR in 1/3 evaluable pts. 21 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.