Abstract CT087: Concentration-dependent early anti-vascular and anti-tumor effects of itraconazole in non-small cell lung cancer (NSCLC)

Abstract

Introduction: Itraconazole has been repurposed as an anti-cancer therapeutic agent for multiple malignancies, including prostate cancer, and basal cell carcinoma, and lung cancer. In preclinical models, itraconazole has antiangiogenic properties and reduces Hedgehog (Hh) pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. Methods: Patients who had NSCLC planned for surgical resection were administered 10-14 days of itraconazole 300 mg orally twice daily. Prior to and at the end of therapy, patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic (PK) and pharmacodynamic analyses. Tissue from pre-treatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyl-itraconazole concentration, as well as vascular and Hh pathway biomarkers. Results: A total of 13 patients were enrolled, of whom 8 completed the course of itraconazole and all biomarker studies. Itraconazole was generally well tolerated. Steady state plasma concentrations of itraconazole and hydroxyl-itraconazole demonstrated low intra-patient variability, but there was a six-fold difference in AUC (area under contrast curve) between patients. Itraconazole treatment did not alter transcription of GLI1 (P=0.20) and PTCH1 (P=0.34) mRNA in skin biopsies. There was a significant association between itraconazole PK and (a) tumor volume reduction (Spearman rank correlation -0.71; P=0.05), and (b) tumor perfusion (Ktrans) (correlation -0.71; P=0.01). Changes in IL-1b, G-CSF, and GM-CSF concentrations were significantly correlated with tumor volume reduction. Conclusions: Itraconazole demonstrates exposure-dependent early anti-vascular and anti-tumor effects in patients with NSCLC. However, it appears to have little activity against the Hh pathway. As interest in vascular-directed therapies re-emerges in this disease, itraconazole may offer a relatively inexpensive, convenient, and well-tolerated option. Funding: Department of Defense (DOD) W81XWH-13-LCRP-CEA Lung Cancer Research Program Clinical Exploration Award Citation Format: David E. Gerber, Farjana J. Fattah, Rolf A. Brekken, Rachael Skelton, Jessica Saltarski, Chul Ahn, Kemp H. Kernstine, Chyndhri Padmanabhan, Vaidehi Chemburkar, Sahba Kasiri, Rajareddy Kallem, Indhumathy Subramaniyan, Qing Yuan, Quyen N. Do, Yin Xi, Ivan Pedrosa, William C. Putnam, James Kim. Concentration-dependent early anti-vascular and anti-tumor effects of itraconazole in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT087.