Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

Abstract

Purpose: The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.Experimental Design: Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m 2 , 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 at 50 mg/m 2 , grade 3 tumor pain/grade 3 hypertension at 60 mg/m 2 , and the RP2D was 50 mg/m 2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (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 patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. Conclusions:The recommended schedule for single-agent ombrabulin is 50 mg/m 2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity.

A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours

“…As expected, prominent toxicities associated with docetaxel were dose-dependent grade 3-4 neutropaenia and leukopaenia. Common grade 1–2 non-haematological toxicities such as asthaenia, nausea, vomiting, diarrhoea, and neuropathy are coherent with the toxicity profiles of both docetaxel (75 and 100 mg m −2 ) and ombrabulin (Sessa et al , 2013), as was the higher frequency of diarrhoea, nail disorders, oedema, and neuropathy with 100 mg m −2 docetaxel compared with 75 mg m −2 (Extra et al , 1993; Harvey et al , 2006). Other ombrabulin-related toxicities such as headache and abdominal pain were reported but were only mild (grade 1–2).…”

“…Neutropaenic complications are associated with docetaxel, but were not reported with single-agent ombrabulin (Sessa et al , 2013). Headache and fatigue were frequent with ombrabulin, and grade 3 thrombosis occurred at the highest ombrabulin single-agent dose evaluated (50 mg m −2 ), although none of these toxicities were dose-limiting with ombrabulin monotherapy.…”

“…In a phase I ombrabulin single-agent study, abdominal pain, tumour pain, and hypertension were dose-limiting and 50 mg m −2 was established as the recommended dose (Sessa et al , 2013). The current two-step phase I study was designed to determine the recommended phase II ombrabulin dose (RP2D) for use in combination with two standard docetaxel doses (75 and 100 mg m −2 ).…”

Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight

“…A phase II trial is currently ongoing to evaluate the safety and efficacy of pazopanib in combination with an oxaliplatinbased therapy as first-line combination for patients with advanced gastric cancer [112]. Ombrabulin is a novel vascular disrupting agent being investigated in phase I trials including gastrointestinal cancers [113,114].…”

Recent Advances in Vascular Disrupting Agents in Cancer Therapy

“…A recent study, for the first time describes its clinical evaluation when administered as monotherapy in patients with advanced solid tumors. The results indicate a promising activity as antitumor agent and in addition preliminary results show increases in circulating endothelial cells, matrix metalloproteinases and VEGF, following AVE8062 administration [62]. However, despite the first promising results, phase III trials on first-line NSCLC and second-line soft-tissue sarcoma failed, and AVE8062 development was stopped [63,64].…”