Dodecafluoropentane Emulsion as a Radiosensitizer in Glioblastoma Multiforme

Abstract

Purpose: Glioblastoma multiforme (GBM) is a hypoxic tumor resistant to radiotherapy. The purpose of this study was to assess the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM.

Experimental design: In this multicenter phase Ib/II dose-escalation study, patients were administered DDFPe via intravenous infusion (0.05, 0.10, or 0.17 mL/kg) while breathing supplemental oxygen prior to each 2 Gy fraction of radiotherapy (30 fractions over 6 weeks). Patients also received standard-of-care chemotherapy [temozolomide (TMZ)]. Serial MRI scans were taken to monitor disease response. Adverse events were recorded and graded. TOLD (tissue oxygenation level-dependent) contrast MRI was obtained to validate modulation of tumor hypoxia.

Results: Eleven patients were enrolled. DDFPe combined with radiotherapy and TMZ was well tolerated in most patients. Two patients developed delayed grade 3 radiation necrosis during dose escalation, one each at 0.1 and 0.17 mL/kg of DDFPe. Subsequent patients were treated at the 0.1 mL/kg dose level. Kaplan-Meier analysis showed a median overall survival of 19.4 months and a median progression-free survival of 9.6 months, which compares favorably to historical controls. Among 6 patients evaluable for TOLD MRI, a statistically significant reduction in tumor T₁ was observed after DDFPe treatment.

Conclusions: This trial, although small, showed that the use of DDFPe as a radiosensitizer in patients with GBM was generally safe and may provide a survival benefit. This is also the first time than TOLD MRI has shown reversal of tumor hypoxia in a clinical trial in patients. The recommended dose for phase II evaluation is 0.1 mL/kg DDFPe.Trial Registration: NCT02189109.

Significance: This study shows that DDFPe can be safely administered to patients, and it is the first-in-human study to show reversal of hypoxia in GBM as measured by TOLD MRI. This strategy is being used in a larger phase II/III trial which will hopefully show a survival benefit by adding DDFPe during the course of fractionated radiation and concurrent chemotherapy.

FIGURE 1

Kaplan–Meier analysis of PFS (left) and OS (right) for all 11 patients and for the 9 patients with IDHwt.

FIGURE 2

Swimmer plot for patients with GBM treated with DDFPe, radiotherapy, and TMZ, showing PD and survival in relation to tumor MGMT promoter methylation status (methylated indicated by dark gray bars and unmethylated by light gray bars) and IDH1 mutation status. WT, wild type IDH1; Mut, R132H IDH1 mutation present; PD, progressive disease.

FIGURE 3

TOLD MRI of patient receiving 0.17 mL/kg DDFPe pretreatment (A) and posttreatment (B) shows reversal of tumor hypoxia. T1 of tumor (mean ± SD) was 1,454 ± 75 ms preadministration of DDFPe and decreased to 1,281 ± 77 ms after treatment. NMR relaxation measurements before and after infusion of DDFPe (C). NMR T1 measurements represent mean ± SD for the 4 patients encompassing tumor or contralateral normal brain imaged at 1.5 T. Baseline measurements (blue) were performed before administration of DDFPe, and postmeasurements (red) were made following intravenous administration of DDFPe, while patients breathed oxygen or carbogen following irradiation. Normal brain tissue showed no significant response (P = 0.70), while tumor showed significant change following administration of DDFPe and irradiation (P = 0.0059). Considering all measurements, tumor tissues had significantly longer T1 relaxation times than normal brain (P < 0.0001). At baseline brain T1 was significantly shorter than tumor (P < 0.0001) and this remained so after administering DDFPe (P = 0.0045).