A Phase 1 accelerated titration dose escalation study of the vascular disrupting agent NPI-2358 utilizing DCE-MRI.

3987 NPI-2358 is a novel tumor vascular disrupting agent acting on β-tubulin that destabilizes tumor vascular endothelial cells with an additional direct cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in multiple murine tumor models. NPI-2358 is particularly effective as a single agent in models for breast tumors and sarcomas and in combinations with irinotecan (colorectal model), paclitaxel (breast model) and docetaxel (NSCLC model). A Phase 1 study of NPI-2358 is being conducted in patients with solid tumors and lymphomas. In addition to standard safety monitoring studies and pharmacokinetics, DCE-MRI is being utilized as a pharmacodynamic measure of tumor blood flow. An improved two-compartment model is utilized which incorporates motion correction and an automated arterial input function. This is expected to improve the accuracy and reproducibility in the estimation of the volume transfer constant (Ktrans) by eliminating variability associated with subject motion, contrast injection, and cardiac output. Patients in this study were treated with NPI-2358 administered as a weekly IV infusion. The dose of NPI-2358 is escalated in cohorts of 1-6 patients dependent on observed adverse events. In addition to weekly safety monitoring (including ECGs and blood pressure), echocardiography and pharmacokinetics were performed on Days 1 and 15 (D1 & D15), and a DCE-MRI obtained 4 hours after the first dose was compared to baseline. The dose has been escalated from 2 mg/m2 to 9 mg/m2 without evidence of dose-limiting toxicity or other significant toxicities including cardiovascular or neurotoxicity. D15 Cmax and AUClast have increased linearly from 16.2 ng/ml to 33.6 ng/ml, and from 54.3 ng/ml*hr to 95.4 ng/ml*hr respectively, without evidence of accumulation. The average T1/2 is 4.5 hours. Intrapatient values for Ktrans appear highly reproducible.