P3-154: Dynamic contrast–enhanced (DCE) MRI imaging biomarker in Phase I study with imatinib (I) and cisplatin (C) plus docetaxel (D) in patients with advanced non–small cell lung cancer (NSCLC)

Abstract

Imatinib inhibits activated PDGF-Rβ and down-regulates VEGF resulting in decreased angiogenesis and improved blood flow favoring enhanced tumor drug delivery. 1) determine the MTD for the combination of imatinib and cisplatin plus docetaxel in NSCLC pts, 2) describe non-dose limiting toxicities (non-DLT), 3) evaluate for feasibility and changes tumor angiogenesis measurement by DCE-MRI after treatment with imatinib. DCE-MRI detects specific properties of vascular beds by virtue of the differential distribution of contrast media in normal and pathological regions. Eligibility: NSCLC with tumor expression of p-PDGF-Rβ. DCE-MRI was performed before and after 7 daily doses of imatinib alone (lead-in) followed by cisplatin plus docetexel on day 1, every 3 weeks. Once daily imatinib was given with each cisplatin plus docetaxel cycle, on days -5 to +2. Standardized hemodynamic parameters (Ktrans, Ve, Kep) were acquired from DCE-MRI. 14 enrolled pts (9 M, 5 F) were evaluable for toxicity and 13 for response. Six pts were treated at dose level 1 (C+D 60/60 mg/m2, and I 300 mg); one DLT (febrile neutropenia) was seen; there were no DLTs in cohort 2 (60/60 mg/m2 and I 400mg; n=3), and two DLTs were observed in cohort 3 (70/70 mg/m≥ and I 400mg; n=5) - febrile neutropenia and grade 4 diarrhea. For all cohorts, grade 3 and 4 toxicities were: fatigue (7%), nausea (14%), neutropenia (14%), elevated creatinine (7%), and dispnea (7%). Two pts (15%) had partial response, and 6/13 pts had stable disease as their best response. DCE-MRI demonstrated trend in decrease of Ve after 7-day treatment with imatinib (p=0.088). MTD for imatinib and cisplatin plus docetaxel in chemo naïve NSCLC pts is 400 mg and 60/60 mg/m≥, respectively. More, DCE-MRI is feasible in NSCLC pts. DCE-MRI measured reduction in tumor extracellular extravascular space (Ve) suggests decrease in intra-tumoral pres-sure after PDGF-Rβ inhibition, which could mean improvement in tumor drug delivery. Further studies exploring DCE-MRI as an imaging biomarker-predictor to antiangiogenic therapy in patients with NSCLC are ongoing.