Phase I dose escalation, toxicity and dynamic contrast-enhanced (DCE) MRI imaging biomarker study of first line treatment with imatinib (I) and cisplatin (C) plus docetaxel (D) in patients with advanced non-small cell lung cancer (NSCLC)

Abstract

18056 Background: Imatinib (I) inhibits activated PDGF-Rβ and down-regulates VEGF resulting in decreased angiogenesis and improved blood flow favoring enhanced tumor drug delivery in lung cancer xenoagrafts. Objectives: 1) determine the MTD for the combination of I and C plus D in NSCLC pts, 2) describe non-dose limiting toxicities (non-DLT), 3) evaluate for feasibility and changes in blood flow/permeability measurement by DCE-MRI after treatment with I, and 4) explore the relationship between measured DCE-MRI parameters and proangiogenic plasma tumor markers PDGF-BB, VEGF, PAI1, ANG2, OPN, and MMP1. Methods: Eligibility: NSCLC with tumor expression of p-PDGF-Rβ. DCE-MRI was performed before and after 7 daily doses of I alone (lead-in) followed by C plus D on day 1, every 3 weeks. Once daily I was given with each C plus D cycle, on days -5 to +2. Standardized hemodynamic parameters (Ktrans, Ve, Kep) were acquired from DCE-MRI. Enrolled patients’ plasma was analyzed by ELISA to determine plasma tumor markers’ level. Results: 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 400 mg; n=3), and two DLTs were observed in cohort 3 (70/70 mg/m2 and I 400 mg; 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 I (p=0.088). Exploratory analysis revealed a significant correlation of: both ANG2 and OPN with Ve (p=0.02 and 0.05 respectively), MMP1 with Kep (p=0.03), and VEGF with Ktrans (p=0.02). Conclusions: MTD for I and C plus D in chemo naïve NSCLC pts is 400 mg and 60/60 mg/m2, respectively. More, DCE-MRI is feasible in NSCLC pts. Phase II study is open and currently enrolling with continues exploration of DCE-MRI as a predictive imaging biomarker, collectively with tumor proangiogenic markers. No significant financial relationships to disclose.