Early evidence of tolerability and clinical activity from a phase I study of TRC105 (anti-CD105 antibody) in patients with advanced refractory cancer

Abstract

3518 Background: CD105 (endoglin) is an angiogenic membrane protein that is over-expressed on proliferating vasculature in solid tumors and up-regulated following anti-VEGF therapy. TRC105 is a human/murine chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition, ADCC, and apoptosis. Methods: The safety and PK of TRC105 were evaluated in patients with refractory cancer. Subjects were to have adequate organ function and no CNS or central thoracic tumors. TRC105 was escalated in cohorts of 3–6 patients to a maximum feasible dose of 1.0 mg/kg i.v. every 2 weeks. Results: 19 ECOG PS 0–1 patients received TRC105 at doses between 0.01–1.0 mg/kg, including 11 men and 8 women aged 37 to 79 years (median 59). One patient experienced dose-limiting toxicity (DLT) at 0.1 mg/kg of grade 4 gastric ulcer bleeding on Day 4 which resolved spontaneously. No other grade 3 or 4 adverse events were reported. Possibly related grade 1–2 adverse events were rare including fatigue, anemia, proteinuria, dysgeusia, diarrhea, flushing, hyperuricemia and intermittent postcoital vaginal bleeding. One patient with castrate-refractory prostate cancer remains on study after 13 months of TRC105 at 0.01 mg/kg with a complete PSA response and bone scan normalization. In addition, 6-month stable disease was seen in a patient with ovarian cancer (CA125 decrease of 16%). Best response also included stable disease (n = 3) and progression (n = 14). Serum TRC105 concentrations expected to saturate CD105 binding sites (> 0.2 ug/mL) were achieved at a dose of 0.3 mg/kg, and concentrations > 10 ug/mL were achieved at 1.0 mg/kg. HAMA became detectable in 1 patient after 3 months of TRC105 therapy. Conclusions: TRC105 is tolerated at doses with evidence of clinical activity. Additional monotherapy and combination studies are planned. [Table: see text]