A phase 1 dynamic accelerated titration dose escalation study of the vascular disrupting agent NPI-2358

14097 Background: 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 and also potentiates the effects of chemotherapeutic agents. Preclinical data indicate NPI-2358 may have advantages in terms of safety profile and activity (tumor blood flow remains markedly reduced after 24 hours). Methods: A Phase 1 study of NPI-2358 is being conducted in patients with solid tumors and lymphomas. Patients in this study were treated with NPI-2358 administered as a weekly IV infusion for 3 weeks in 4-week cycles. Eight subjects have been enrolled. The dose of NPI-2358 was escalated in cohorts of 1–3 patients dependent on observed adverse events (any cohort may consist of 1 patient provided no =Grade 2 AE is reported in the prior cohort). A cohort is expanded to 6 patients if a DLT is reported. Escalation was conducted in 100% intervals, and decreased to 50% intervals once a Grade 2 adverse event was reported. In addition to weekly safety monitoring (including ECGs, Troponin I, 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. Results: The dose has been escalated from 2 mg/m2 to 9 mg/m2 (predicted minimum efficacious dose = 7.5 mg/m2) without evidence of dose-limiting toxicity or other significant toxicities including cardiovascular or neurotoxicity. Intrapatient values for Ktrans from DCE-MRIs appear highly reproducible. No responses have been reported, however, one patient with pancreatic adenocarcinoma has had stable disease (SD) for 3 cycles and continues to receive NPI-2358. Average Cmax and AUClast have increased from 16.2 ng/ml to 147 ng/ml, and from 101 to 360 ng/ml*hr respectively. No drug accumulation was observed; T1/2 was 4.2 ±1.9 h, clearance was 45 ±12 L/h and distributive volume was 251±57 L. Conclusions: NPI-2358 is well tolerated at doses above the minimum predicted efficacious dose. PK data show increasing Cmax and AUC with dose escalation and no drug accumulation on a weekly schedule. No significant financial relationships to disclose.