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

Abstract

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.

Conflict of interest statement

Disclosure of potential conflicts of interest:

BME: Consulting/Advisory: MedQIA, Genentech/Roche, Agios, Siemens, Janssen, Medicenna, Imaging Endpoints, Novogen, Northwest Biopharmaceuticals, Image Analysis Group, Oncoceutics, Beigene, Tocagen, VBL Therapeutics. Research Grants: Siemens, Janssen, VBL Therapeutics.

JY: None

CR: None

DAN: None

AC: None

JS: Employee of Kazia Therapeutics Limited.

JG: Employee of Kazia Therapeutics Limited.

AO: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

LM: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

JR: Non-financial support and reasonable reimbursement for travel: European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, Glaxo Smith Kline. Consulting and travel fees: Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma (including serving on the scientific advisory board from 2015-present). Research funding: Bayer, Novartis. Serving as investigator in clinical trials: Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, Glaxo Smith Kline, IPSEN. Travel fees: ESMO, US Department of Defense, Louisiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC).

ERG: None

TC: Advisory role: Abbvie, Agios, Amgen, Bayer, Boehinger Ingelheim, Boston Biomedical, Celgene, Deciphera, Del Mar Pharmaceuticals Genentech/Roche, GW Pharma, Karyopharm, Kiyatec, Medscape ,Merck, Odonate Therapeutics, Pascal Biosciences, Tocagen, Trizel, VBI , VBL Therapeutics. Stock options: Notable labs. Board of Directors: Global Coalition for Adaptive Research (501c3).

PYW: Consulting or Advisory role: AbbVie, Agios, Angiochem, AstraZeneca, Cavion, Celldex, Exelixis, Astra Zeneca, Bayer, Blue Earth Diagnostics, Immunomic Therapeutics, Karyopharm, Kiyatec, Merck, Prime Oncology, Puma, Taiho, Tocagen, Vascular Biogenics, Deciphera, VBI Vaccines. Research support: Agios, Astra Zeneca, Beigene, Eli Lily, Genentech/Roche, GlaxoSmithKline, Karyopharm Therapeutics, Midatech, Momenta Pharmaceuticals, Kazia, MediciNova, Merck, Novartis, Novocure, Regeneron, Oncoceutics, Prime Oncology, Sanofi, Sigma-Tau-Aventis, Vascular Biogenics. VBI Vaccines. Speakers’ Bureau: Merck, Prime Oncology. DSMB: Tocagen.

©2020 American Association for Cancer Research.

Figures

Fig. 1:. Data flow diagram describing available imaging data for each parameter.

A total of 47 patients were enrolled in the current trial. Of which, all patients had anatomic imaging, but only a subset of patients had MRI and PET imaging data available and of sufficient quality for the current study.

Fig. 2:. Example MR-PET imaging response in a 47-year-old female patient with recurrent GBM treated with 45mg of GDC-0084.

A) Baseline, pre-treatment and B) 2 month post-treatment multi-parametric MR-PET images are shown, including T2-weighted fluid attenuated inversion recovery (FLAIR), post-contrast T1-weighted images, T1 digital subtraction maps, normalized 18F-FDG PET SUV maps fused to anatomic MR images, apparent diffusion coefficient (ADC) maps, fractional anisotropy (FA) maps, as well as maps of Ktrans, plasma volume fraction (vp), and relative cerebral blood volume (rCBV). C) Pharmacokinetic characteristics during the first 24 hours after the 1st dose of GDC-0084 in this patient. Red arrows show reduction in contrast enhancing tumor burden after treatment.

Fig. 3:. Multi-parametric MR-PET imaging responses for various oral dose levels of GDC-0084.

Change in A) contrast enhancing tumor volume, B) median 18F-FDG uptake relative to white matter, C) median ADC, D) median FA, E) median Ktrans, F) median vp, and G) median rCBV for low (2–8mg), medium (15–30mg), and high (45–65mg) oral dose levels of GDC-0084.

Fig. 4:. Correlation between multi-parametric MR-PET imaging responses and Cmax.

Correlation between measured Cmax and change in A) contrast enhancing tumor volume, B) median 18F-FDG uptake relative to white matter, C) median ADC, D) median FA, E) median Ktrans, F) median vp, and G) median rCBV. H) Model predictions of Cmax using a linear combination of multi-parametric MR-PET imaging measurements compared with measured values of Cmax.

Fig. 5:. Correlation between multi-parametric MR-PET imaging responses and AUC.

Correlation between measured AUC and change in A) contrast enhancing tumor volume, B) median 18F-FDG uptake relative to white matter, C) median ADC, D) median FA, E) median Ktrans, F) median vp, and G) median rCBV. H) Model predictions of AUC using a linear combination of multi-parametric MR-PET imaging measurements compared with measured values of Cmax.

Fig. 6:. Difference in progression-free survival (PFS) between multi-parametric MR-PET imaging estimates of high and low concentration and exposure to GDC-0084.

A) Difference in PFS between imaging estimates of high Cmax (>0.1 uM) and low Cmax (<0.1 uM) (Log-rank, P=0.0039). B) Difference in PFS between imaging estimates of high AUC (>1.25 uM*hr) and low AUC (<1.25 uM*hr) (Log-rank, P=0.0296).