Simpson, Brian E

268 Background: TRC105, an endoglin antibody, potentiates the activity of sorafenib (S) in preclinical HCC models, and TRC105 + S demonstrated a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC pts ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently. Methods: P1: Compare wkly TRC105 dosing vs four wkly doses followed by every other wkly dosing + S 800 mg daily. P2: Four objective responses are required in 21 pts to reject the null hypothesis that the true response rate probability is < 5% with an alpha level of 0.1 and 80% power. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Thirteen pts were enrolled in phase 1b at TRC105 10 mg/kg wkly for four doses and 15 mg/kg every other week thereafter + S. Mean serum levels of TRC105 exceeded the target conc. following 4 wkly doses of TRC105 at 10 mg/kg (mean = 34 µg/ml, range BLOQ-80). Mean trough conc. decreased following every other week dosing (mean = 13 µg/ml, range BLOQ-31), resulting in infusion reactions or a continued requirement for premedication. Therefore, wkly dosing of TRC105 at 10 mg/kg is the recommended Phase 2 dose. ADA were detected in 10 of 14 pts and correlated with lower than expected PK conc. Common TRC105 related AEs included ≤ G2 epistaxis, ≤ G2 fatigue and ≤ G2 headache. Common S related AEs included ≤ G3 fatigue, ≤ G3 hand foot syndrome and ≤G2 epistaxis. A total of 3 out of 14 evaluable patients (21%) enrolled in phase 1 and 2 achieved durable PR, 2 of these ongoing at week 45 and 17. Conclusions: TRC105 dosed at 10 mg/kg wkly was required to achieve target conc. due to higher clearance in HCC pts, which may have been influenced by a higher rate of ADA compared to studies of TRC105 in other tumor types. The combination of TRC105 + S demonstrated encouraging signs of activity, including durable PR in 2/9 evaluable pts in Phase 1b and 1/5 pts thus far in Phase 2. An additional 16 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.

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.