Phase 1 clinical trials of NPI-2358 (a novel vascular disrupting agent) in patients with solid tumors and lymphomas

B14 Background: NPI-2358 is a novel tumor vascular disrupting agent (VDA) 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 and radiation. Preclinical data suggest 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 advanced solid tumors and lymphomas. Patients enrolled were treated with a weekly IV infusion of NPI-2358 for 3 weeks in 4-week cycles. Seventeen subjects have been enrolled. The study uses a dynamic accelerated dose titration design in which the dose of NPI-2358 is escalated in cohorts of patients dependent on observed adverse events. Any cohort may consist of 1 patient provided no≥Grade 2 AE is reported in the prior cohort. If a ≥Grade 2 AE is reported in the prior cohort, the cohort consists of at least 3 patients. A cohort is expanded to 6 patients if a DLT is reported. Escalation was initially 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. Additional DCE-MRIs may also be performed on D2 and every 2 cycles.
 Results: The dose has been escalated from 2 mg/m ² to 20 mg/m ² (predicted minimum efficacious dose = 7.5 mg/m ² ). One DLT of pulmonary embolus occurred at 13.5 mg/m ² . Nausea, tumor pain and transient elevations in blood pressure have been reported. Significant toxicities likely to be related to drug, including cardiac (assessed by echocardiography, ECG and Troponin I) or neurotoxicity, have not been reported. Intrapatient values for Ktrans from DCE-MRIs have been highly reproducible and a consistent 12-23% decrease in Ktrans was seen in all patients evaluated at 13.5 mg/m ² . No responses have been reported, however, three patients had stable disease (SD) for two or more cycles: pancreatic adenocarcinoma (4 cycles), colorectal carcinoma (2 cycles) and squamous cell (2 cycles). Average Cmax and AUC last have increased from 34 to 223 ng/ml and from 101 to 1159 ng/ml*hr respectively. No drug accumulation was observed; for all patients T1/2 was 5.3 ±2.98 h, CL was 40.7±30L/h and distributive volume was 229±57 L.
 Conclusions: NPI-2358 is well tolerated at doses above the minimum predicted efficacious dose. Systemic exposure assessed by Cmax and AUC increased with dose escalation and no drug accumulation was evident with weekly administration. Pharmacodynamic measures (DCE-MRI) suggest effects of the drug on tumor blood flow at current doses.