Phase 1 safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors
Mené sur 105 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose recommandée de l'ombrabuline et identifie des biomarqueurs potentiels de la réponse thérapeutique
Purpose: The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase 1 dose escalation study was designed to determine the recommended phase 2 dose (RP2D) of single agent ombrabulin administered once every 3 weeks in patients with advanced solid malignancies. Experimental design: Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m², with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Results: Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation; grade 3 abdominal pain (50 mg/m²) and grade 3 tumor pain/grade 3 hypertension (60 mg/m²) and the RP2D was 50 mg/m² (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia and lymphopenia. No clinically significant QTc prolongations or LVEF decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A rectal cancer patient had a partial response and eight patients had stable disease lasting ≥4 months. Circulating endothelial cells (CECs), VEGF and MMP-9 levels increased significantly 6-10 hours post-infusion in a subset of patients. Conclusions: The recommended schedule for single agent ombrabulin is 50 mg/m² every 3 weeks. CECs, VEGF and MMP-9 are potential biomarkers of ombrabulin activity