American Association for Cancer Research
10780432ccr193817-sup-232819_2_supp_6154816_q7txry.pdf (2.9 MB)

Supplemental Figure 2 from Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma

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journal contribution
posted on 2023-03-31, 21:49 authored by Benjamin M. Ellingson, Jingwen Yao, Catalina Raymond, David A. Nathanson, Ararat Chakhoyan, Jeremy Simpson, James S. Garner, Alan G. Olivero, Lars U. Mueller, Jordi Rodon, Elizabeth Gerstner, Timothy F. Cloughesy, Patrick Y. Wen

Correlation between multi-parametric MR-PET imaging changes before and after GDC-0084. A) Pearson's correlation coefficient (R) and B) resulting p-values describing the association between all imaging measurements. No significant correlations (P<0.05) were observed.



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 (Cmax) was associated with a decrease in enhancing tumor volume (P = 0.0287) and an increase in fractional anisotropy (FA; P = 0.0418). Posttreatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with Cmax. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV was able to estimate both Cmax (R2 = 0.4113; P < 0.0001) and drug exposure (AUC; R2 = 0.3481; P < 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated Cmax > 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 (P = 0.0039 and P = 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.

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