Connelly, Jennifer

2016 Background: Bevacizumab therapy (Bev) for recurrent glioblastoma (rGBM) has not demonstrated improved overall survival (OS) in randomized clinical trials. However, single-center and preliminary multi-center studies suggest that relative cerebral blood volume (rCBV) measured with dynamic susceptibility contrast MRI (DSC-MRI) at baseline or shortly after treatment initiation may predict response to Bev. The primary aim of ECOG-ACRIN EAF151 was to evaluate whether early binary change in rCBV, assessed 2–3 weeks after initiation of Bev-containing therapy, identifies patients with an OS benefit of ≥4 mos. Pre-specified secondary aims assessed baseline rCBV; post-hoc exploratory analyses examined early post-Rx rCBV. Methods: A prospective, phase II multi-center trial without randomization enrolled subjects with rGBM receiving their first Bev-containing therapy. Progression was determined by local sites (RANO criteria; MRI within 28 days of registration, ≥42 days since end of chemoradiation). Baseline (S0) and follow-up (S1) DSC-MRI were performed before the first Bev infusion (within 3 days), and 12-25 days post-infusion but before the second infusion. Anatomic MRI and DSC-MRI (double-dose Gadavist injection, full-dose preload) complied with recommended protocols. Mean normalized (nRCBV) and standardized (sRCBV) rCBV were extracted from contrast-enhancing tumor ROIs. A 2-sided logrank test (α=0.1) was used to test the primary aim (change in mean nRCBV from S0 to S1, ≥0 vs. <0). Cox regression with restricted cubic splines was used to assess the association between continuous rCBV markers and OS. Results: 146 subjects were accrued from 33 sites. 134 completed S0 and 118 completed both S0 and S1. After exclusion of uninterpretable scans, 107 were evaluable for change in rCBV, and 124 for baseline rCBV. There was no statistically significant difference in OS between subjects with binary increase (n=40; median OS 8.0 mos [90% CI 5.5–9.2]) vs. decrease (n=67; 7.9 mos [90% CI 6.3–10.3]) in mean nRCBV (p=0.67). Based on the spline fits, we observed a strong nonlinear association between OS and continuous nRCBV and sRCBV at both S0 and S1: low marker values are associated with lower risk, but beyond a threshold, higher values are not associated with greater risk. As an exploratory analysis, we estimated optimal cut points (nRCBV: S0=1.11, S1=1.16; sRCBV: S0=1.13, S1=0.99) and found that subjects whose S1 rCBV decreased below threshold had a median OS 2.7 mos (nRCBV, HR 0.61 [90% CI 0.41–0.88]) and 5.2 mos (sRCBV, HR 0.43 [90% CI 0.28–0.63]) longer than subjects whose rCBV either increased or did not decrease below threshold. Conclusions: EAF151 prospectively evaluated whether DSC-MRI markers predict OS in patients with rGBM treated with Bev. Although the change in these markers was not predictive, both baseline and early post-Rx markers were predictive of OS. Clinical trial information: NCT03115333 .

PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

Abstract Dynamic susceptibility contrast (DSC) MRI measures of brain tumor cerebral blood volume (CBV) are able to predict grade, overall survival and response to treatment. Wide-spread acceptance of DSC-MRI has been challenged by the need to balance contrast agent dose and CBV accuracy. The goal of this study was to identify and validate single-dose, BTIP compliant, DSC-MRI protocols. Using a validated, patient-based DRO, we evaluated CBV accuracy across a range of acquisition parameters (field strength, TR, TE, flip angle, multi-echo acquisitions, dosing protocols) and post-processing steps. To validate the optimal protocols, we next collected DSC-MRI data following ASFNR’s recommended “double – dose” approach, where a single-dose preload (to minimize T1 effects) is given prior to a second bolus injection (for DSC-MRI data acquisition). The single-dose DSC-MRI data was collected during the preload bolus injection. Consistency of the derived CBV data, visual agreement and data characteristics (e.g. CNR) was statistically evaluated. When using a single-dose and routine single-echo pulse sequence, the DRO analysis found that a low flip angle (LFA = 30o) and 30ms TE provided the highest CBV accuracy (concordance correlation coefficient (CCC) = 0.92) and precision (coefficient of variation (CV) = 8.2%)). For comparison, the maximum accuracy found with the DRO utilizes a double-dose injection protocol and yielded a CCC of 0.98 and CV of 6.8%. Single-dose, multi-echo acquisitions provided higher accuracy than the LFA data and matched that found with the double-dose approach. In patients (data collection ongoing), the agreement between single-dose LFA (n > 40) or multi-echo (n > 40) based CBV values and the reference double-dose approach was very high (CCC > 0.94) and were statistically equivalent. Optimized single-dose DSC-MRI protocols provide highly accurate CBV data, use lower doses of contrast agent, and simplify scan procedures, indicating their potential for robust use in clinical practice and trials.