First-in-human dose escalation safety and pharmacokinetic (PK) trial of a novel intravenous (IV) thrombospondin-1 (TSP-1) mimetic humanized monoclonal CovX Body (CVX-045) in patients (pts) with advanced solid tumors
3524 Background: CVX-045 is a recombinant humanized monoclonal antibody fused to two TSP-1 mimetic, nonamer peptides. CVX-045 inhibits endothelial cell migration in vitro, and is anti-angiogenic in vivo. A TSP-1 mimetic CovX Body has potential as an anti-angiogenic intervention via a previously unexploited mode of action. Methods: Pts with advanced solid tumors and no known bleeding risk received CVX-045 administered in 3 pt cohorts (0.3, 1, 3, 6, 12 and 18 mg/kg) by once weekly IV infusions (4 wk cycles) over 90 min lowered to 30 min upon individual tolerability. DLTs were grade ≥ 3 AEs in cycle 1 not directly related to tumor progression. MTD was highest dose at which 0/3 or 1/6 patients experience DLT. Serum PK assessed by highly specific ELISA. DCE-MRI pre-dose, on Day 2–4 and Day 28, in pts dosed at 3 mg/kg and higher. Results: 18 pts (M/F 6/12) were treated, median age 58.5 years (range 33–82), median prior regimens 7 (range 2–19), ECOG performance status 0–1, and median weeks on study at cut off 9 (range 3–22). No cycle 1 DLTs were observed. No obvious dose dependencies related to safety. Common adverse events (Grade 1–2) included gastrointestinal (abdominal pain, nausea, anorexia, flatulence, diarrhea and constipation), anemia, headache, fatigue and general muscle weakness. One case of suspected infusion reaction (Grade 1) in a patient receiving the highest dose (18 mg/kg) administered over 60 minutes. 6 serious AEs (Grade ≥ 3), only one of which, a case of radiation pneumonitis complicated by infectious pneumonia, was thought to be possibly drug related. Cmax and AUC increased linearly with dose, mean β T1/2 98.5 hrs. DCE-MRI showed effects on flow (21 - 42% decr. in Ktrans) but not permeability (AUCBN(90)) in 2/3 pts in 12 mg/kg group and 1 pt in 6 mg/kg group. RECIST: unconfirmed PR in 1 pt with liver mets and SD currently 8 to 16 weeks in 5/12 pts. 12 mg/kg appears to be the appropriate dose for further study. Conclusions: CVX-045 is a well tolerated new therapy targeting angiogenesis by a novel pathway. PK results are consistent with once weekly dosing. There is preliminary evidence by DCE-MRI and RECIST to suggest biologic activity.