Abstract LB-202: Phase 1 dose escalation trial of the novel vascular disrupting agent NPI-2358

Abstract

Abstract Background: NPI-2358 is a novel vascular disrupting agent that inhibits tubulin polymerization leading to tumor vascular endothelial destabilization. NPI-2358 selectively induces tumor vascular collapse resulting in tumor regression and potentiates other oncology agents in preclinical tumor models. Preclinical data suggest NPI-2358 may have advantages in terms of safety profile and activity. Methods: In this study the dose of NPI-2358 was escalated from 2 to 30 mg/m2 in 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 was escalated in cohorts, in which any cohort could consist of 1 patient provided no ≥Grade 2 adverse event is reported in the prior cohort, otherwise the cohort consisted of at least 3 patients. In addition to weekly safety monitoring, ECG, ECHO, and PK were obtained on day 1 and day 15. DCE-MRI were performed at baseline, day 2 then every other cycle and end of study as feasible, to assess changes in tumor blood flow and vascular permeability as reflected in the volume transfer constant (Ktrans). 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 Ktrans by eliminating variability associated with subject motion, contrast injection, and cardiac output. Results: Twenty-five subjects were enrolled in the dose escalation phase. We selected 30 mg/m2 as the RP2D, based on adverse events 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 16-82% decrease in patients evaluated at 30 mg/m2. Decreasing Ktrans over multiple treatment cycles was seen in the two patients that underwent repeat DCE-MRI imaging. 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 AUCtotal have increased from 34 to 610 ng/ml, and from 101 to 3998 ng/ml/hr respectively. No drug accumulation was observed. For all patients T1/2 was 5.8 ±3.2 h, CL was 34.1 ±26 L/h, and Vss was 211±61 L.Conclusions: At the RP2D NPI-2358 produced tolerable toxicities, while eliciting decreases in tumor blood flow by DCE-MRI. Maximum effect on Ktrans appeared to increase with increasing dose and time on treatment. Cmax and AUC increased with dose, without drug accumulation. NPI-2358 is currently proceeding into Phase Ib/II trials in solid tumor malignancies.