Abstract B19: Interim safety results of a randomized phase 2 trial of a tumor vascular disrupting agent fosbretabulin tromethamine (Ca4p) with carboplatin, paclitaxel and bevacizumab in stage IIIB/IV non-squamous non-small cell lung cancer
Authors: Garon Edward B. , Kabbinavar Fairooz , Balkissoon Jai , Lu Shaio-Ping , Neidhart James A. , Gabrail Nash , de Oliveira Moacyr R. 
Published: June 2012

Abstract
Background: Blocking tumor angiogenesis with bevacizumab (Bev) in NSCLC resulted in improved overall survival (OS), progression-free survival (PFS), and response rate (RR) in study E4599. Targeting the abnormal tumor vasculature with the tumor vascular disrupting agent fosbretabulin (CA4P) causes rapid occlusion of existing tumor blood vessels with intratumoral necrosis. Tumor regrowth occurs from viable tumor cells at the outer tumor rim with ongoing angiogenesis. The combination of Bev and CA4P was well tolerated in a completed Phase 1 study of solid tumors with some patients having prolonged stable disease. We hypothesized that the addition of CA4P to chemotherapy and Bev in NSCLC would be well tolerated and result in at least additive antitumor effects.
Methods: Patients with untreated Stage IIIB/IV non-squamous NSCLC and ECOG PS 0–1 are randomized to carboplatin (AUC 6) + paclitaxel (200 mg/m2) + Bev (15 mg/kg) (Arm 1) on Day 1 every 3 weeks for 6 cycles or the same regimen + CA4P (60 mg/m2) on Days 7, 14, 21 every 3 weeks for 6 cycles (Arm 2). Patients without progression continue to receive Bev (Arm 1) or Bev + CA4P (Arm 2) until disease progression; all patients are followed until death. Primary endpoints of the study are safety, tolerability and PFS; secondary endpoints are RR and OS.
Results: From May 2008 to June 2009, 15 patients were treated on each arm. Median age was 67 yrs (range 47–81). Median follow up was 21.3 weeks in Arm 1 and 21.7 weeks in Arm 2. Nine (60%) patients in Arm 1 and seven (47%) patients in Arm 2 completed 6 cycles of therapy. Six patients died: five in arm 1 and one in arm 2. All deaths were from disease progression except one event of fatal hemoptysis in arm 1. Safety analysis was conducted for Arm 1 vs. Arm 2. Grade 3–4 hematologic toxicity: neutropenia (27% vs. 73 %), febrile neutropenia (0% vs. 13%), and thrombocytopenia (20%vs. 20 %). Grade 3–4 non-hematologic toxicity: hypertension (0%vs. 13 %), neuropathy (13% vs. 0 %). No clinically significant QTc prolongation was seen. On arm 2, one patient had asymptomatic ECG changes suggestive of cardiac ischemia and another patient had symptomatic Grade 3 cardiac ischemia; both events resolved within 24 hours. One patient on Arm 2 developed bilateral pulmonary emboli.
Conclusions: An analysis of 30 patients completing at least 1 cycle of therapy showed that the addition of CA4P to carboplatin/paclitaxel/Bev is well tolerated. Observed increase in Grade 3–4 neutropenia resolved without significant dose reductions or discontinuation of therapy. There are no new safety signals or overlapping toxicities with Bev. Clinically significant QTc prolongation has not been seen; rates of cardiac ischemia are low. Most of the deaths due to disease progression occurred in Arm 1. A final analysis will be presented at ASCO 2010.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B19.