Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma.

Abstract

GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. Because these two targets alter tumor vascularity and metabolism, respectively, we hypothesized multiparametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. Multiparametric advanced MR-PET imaging was performed to evaluate physiologic response in a first-in-man, multicenter, phase I, dose-escalation study of GDC-0084 (NCT01547546) in 47 patients with recurrent malignant glioma. Measured maximum concentration (<i>C</i> _max) was associated with a decrease in enhancing tumor volume (<i>P</i> = 0.0287) and an increase in fractional anisotropy (FA; <i>P</i> = 0.0418). Posttreatment tumor volume, ¹⁸F-FDG uptake, K^trans, and relative cerebral blood volume (rCBV) were all correlated with <i>C</i> _max. A linear combination of change in ¹⁸F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, K^trans, v_p, and rCBV was able to estimate both <i>C</i> _max (<i>R²</i> = 0.4113; <i>P</i> < 0.0001) and drug exposure (AUC; <i>R²</i> = 0.3481; <i>P</i> < 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated <i>C</i> _max > 0.1 μmol/L and AUC > 1.25 μmol/L*hour demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (<i>P</i> = 0.0039 and <i>P</i> = 0.0296, respectively). Results from this study suggest composite biomarkers created from multiparametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.