Phase I study of NPI-2358 (a novel vascular disrupting agent) in patients with solid tumors and lymphomas

Abstract

3525 Background: NPI-2358 is a novel vascular disrupting agent (VDA) acting on tubulin dimerization that destabilizes tumor vascular endothelial cells and has cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in murine tumor models and potentiates other oncology agents. Preclinical data suggest NPI-2358 may have advantages in terms of safety profile and activity. Methods: Dose escalation of NPI-2358 was conducted in a phase I trial enrolling patients with advanced solid tumors and lymphomas. Patients were treated with a weekly IV infusion of NPI-2358 for 3 weeks in 4-week cycles. The study utilized a dynamic accelerated dose titration (DADT) design in which the dose of NPI-2358 would be escalated in cohorts from 2 mg/m2 to a recommended phase II Dose (RP2D). Any cohort could consist of 1 patient provided no ≥ Grade 2 adverse event (AE) is reported in the prior cohort. If a ≥ Grade 2 AE is reported in the prior cohort, the cohort consisted of at least 3 patients. In addition to weekly safety monitoring, ECG, ECHO and PK were obtained on D1 & D15. DCE-MRI were utilized to assess changes in tumor blood flow. Results: 25 subjects were enrolled. 30 mg/m2 was selected as the RP2D (predicted minimum efficacious dose = 7.5 mg/m2), based on toxicities of nausea, vomiting, fatigue, fever, tumor pain and transient elevations in blood pressure. DCE-MRI demonstrated decreases in Ktrans beginning at 13.5 mg/m2, and a 16–54% decrease in patients evaluated at 30 mg/m2. Five patients had stable disease for two or more cycles: pancreatic adenocarcinoma (4 cycles), colorectal carcinoma (2 cycles), anal squamous cell carcinoma (3 cycles), adrenalcortical carcinoma (2 cycles) and melanoma (2 cycles). Average Cmax and AUClast have increased from 34 to 468 ng/ml, and from 101 to 1518 ng/ml*hr respectively. No drug accumulation was observed. For all patients T1/2 was 5.3 ±2.8 h, CL was 37.3±28 L/h and Vss was 214±63 L. Conclusions: NPI-2358 generally produced modest toxicity at the RP2D, which was significantly above the predicted efficacious dose and elicited decreases in tumor blood flow by DCE-MRI. Cmax and AUC increased with dose, without drug accumulation. NPI-2358 is currently entering Phase 1b/2 trials in solid tumor malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nereus Nereus Nereus Nereus