Abstract C30: Phase 1/2 study of the vascular disrupting agent (VDA) plinabulin (NPI-2358) combined with docetaxel in patients with non-small cell lung cancer (NSCLC)
Authors: Heist Rebecca , Aren Osvaldo , Millward Michael , Mainwaring Paul , Mita Alain , Mita Monica , Bazhenova Lyudmila , Blum Robert , Polikoff Jonathan , Gadgeel Shirish , Deshmukh Chetan , Llyod G. Kenneth , Reich Steven , Spear Matthew A. 
Published: June 2012

Abstract
Background: Plinabulin is a vascular disrupting agent (VDA) that binds - tubulin, destabilizing tumor vascular endothelial cytoskeletal architecture and leading to selective collapse of established tumor vasculature. With a structure differing from other -tubulin binding VDAs, preclinical studies suggested improvements in toxicology and efficacy leading to clinical assessment of plinabulin. VDAs have been of particular interest given indications of significant activity in NSCLC, as well as potential differentiation from other agents in terms of utility in certain patient subsets such as those with squamous cell carcinoma (SCC) or at risk for bleeding events. Plinabulin was seen to act synergistically with docetaxel in murine models of NSCLC, resulting in the initiation of this clinical trial (the ADVANCE study).
Methods: Patients with advanced NSCLC having received prior chemotherapy were enrolled (patients with other malignancies could be enrolled during the Phase 1 portion). Patients were permitted to have been previously treated with bevacizumab, as well as VEGFR or EGFR targeted agents. Docetaxel (75 mg/m2) was given on Day 1 and plinabulin on Days 1 & 8 in 21-day cycles. During Phase 1, the dose of plinabulin was escalated from the single agent biologic effect dose (BED) of 13.5 mg/m2 to determine a Recommended Phase 2 Dose (RP2D) in combination with docetaxel. During Phase 2, 154 patients are randomized to receive docetaxel with or without plinabulin at the RP2D, with overall survival compared as the primary outcome.
Results: 13 patients were enrolled into the Phase 1 portion, of which 10 had NSCLC. The dose of plinabulin was escalated to 30 mg/m2, thus 30 mg/m2 of plinabulin with 75 mg/m2 docetaxel was selected as the RP2D. Toxicites were as expected with either agent alone. Nausea, vomiting, fatigue, fever, tumor pain, and diarrhea were most frequently seen, with one DLT of nausea, vomiting, dehydration and neutropenia observed at 30 mg/m2. Changes in expected pharmacokinetics of the 2 drugs in combination were not seen, and the best response in patients with evaluable NSCLC was higher with the combination than expected with docetaxel alone, with 6/8 having reductions in tumor measurements and 2/8 reaching partial response (&gt;30% reduction). Based on these outcomes the Phase 2 portion of the study was initiated. Enrollment is half complete, with 77 patients having been enrolled. Patients with all histologies of NSCLC, including SCC are being enrolled. Interim data from these patients will be analyzed in October 2009 and presented.
Conclusions: In this Phase 1/2 evaluation of plinabulin in combination with docetaxel, during the Phase 1 portion PK and safety data did not demonstrate an unexpected toxicities or an adverse drug-drug interaction, and activity was encouraging relative to the 5–10% response rate reported with docetaxel alone in this population. Efficacy and safety are now being compared in the Phase 2 portion with a 1:1 randomization into 2 arms [docetaxel (75 mg/m2) +/− plinabulin (30 mg/m2)].
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C30.