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

by Selleckchem | Jul 22 2023

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 (C max) 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 C max. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV was able to estimate both C max (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 C 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 (P = 0.0039 and P = 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.

Comments:

The provided text describes a study that investigated the use of multiparametric MR-PET imaging in evaluating the response to a drug called GDC-0084 in patients with recurrent malignant gliomas, a type of brain tumor. GDC-0084 is an oral, brain-penetrant small-molecule inhibitor that targets both PI3K and mTOR, two proteins involved in tumor vascularity (formation of blood vessels within tumors) and metabolism, respectively.

The purpose of the study was to assess whether multiparametric MR-PET imaging could be used to measure the response to GDC-0084 treatment, estimate pharmacokinetic (PK) parameters (how the drug is absorbed, distributed, metabolized, and excreted by the body), and predict progression-free survival (PFS) in the patients.

In the study, 47 patients with recurrent malignant glioma participated in a phase I, dose-escalation trial of GDC-0084 (clinical trial identifier: NCT01547546). These patients underwent multiparametric advanced MR-PET imaging to evaluate the physiological response to the treatment.

The results of the study showed that the measured maximum concentration (C max) of GDC-0084 was associated with a decrease in the volume of the enhancing tumor (the part of the tumor that lights up on imaging) and an increase in fractional anisotropy (FA), a measure of the directionality of water diffusion in tissues. Post-treatment tumor volume, 18F-FDG uptake (a measure of glucose metabolism), Ktrans (a measure of blood vessel permeability), and relative cerebral blood volume (rCBV) were all correlated with C max.

The researchers developed a composite multiparametric MR-PET imaging response biomarker by combining changes in various parameters including 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp (blood plasma volume), and rCBV. This biomarker was able to estimate both C max and drug exposure (area under the concentration-time curve, AUC) of GDC-0084.

Furthermore, using this composite biomarker, the study demonstrated that patients with higher estimated C max (>0.1 μmol/L) and AUC (>1.25 μmol/L*hour) had significantly longer progression-free survival (PFS) compared to patients with lower estimated concentration and exposure.

In conclusion, the study findings suggest that the use of composite biomarkers created from multiparametric MR-PET imaging, which target metabolic and physiological processes specific to the drug's mechanism of action, may be valuable in evaluating the efficacy of GDC-0084 treatment. These findings highlight the potential utility of such imaging techniques in larger phase II-III studies for assessing treatment response in patients with malignant gliomas.