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

Purpose: 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.

Patients And Methods: 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.

Results: Measured maximum concentration ( ) was associated with a decrease in enhancing tumor volume ( = 0.0287) and an increase in fractional anisotropy (FA; = 0.0418). Posttreatment tumor volume, F-FDG uptake, K, and relative cerebral blood volume (rCBV) were all correlated with . A linear combination of change in F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, K, v, and rCBV was able to estimate both ( = 0.4113; < 0.0001) and drug exposure (AUC; = 0.3481; < 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated > 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 ( = 0.0039 and = 0.0296, respectively).

Conclusions: 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.