Derek J. Jonker, Leonard Avruch, D. Stewart
Jul 15, 2004
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Journal
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Abstract
3078 Background: Exherin is a novel angiolytic VTA which specifically targets existing tumor vessels. Exherin is a cyclic pentapeptide (CHAVC) which competitively inhibits N-cadherin mediated endothelial cell, pericyte and tumor cell binding. Exherin caused highly-specific tumor angiolysis in multiple murine and xenograft tumor models. We report here preliminary data from the first human safety and pharmacokinetics (PK) study on Exherin. METHODS 13 patients (pts) with refractory solid tumors received 24 cycles of Exherin by bolus injection at 4 dose levels from 50 to 225 mg/m2to define the toxicities (AE) and maximum tolerated dose (MTD) for patients with N-cadherin positive or negative tumors. Dynamic MRI was performed in cohorts 3 to 5 where feasible to assess for changes in tumor perfusion and intra-tumoral hemorrhage. RESULTS Dose escalation has proceeded without reaching MTD. AE > grade 2 considered possibly drug related include tumor pain (n=3) and 1 coronary syndrome in a patient with a previously unknown 99% LCX occlusion. Low grade (≤2) considered probably drug related included fatigue (n=4), hot flushes (n=4), and dysgeusia (n=3). PK data show that the AUC and Cmaxincrease linearly with dose and that the mean terminal t1/2is 84 minutes. [Figure: see text] Conclusions: Exherin has been well tolerated at the doses given. MTD has not been reached. Further dosage escalation, molecular target expression measurement by immunohistochemistry, and MRI data will be presented. [Table: see text].