DDEL-11 - Determining the dose of regadenoson most likely to transiently alter the integrity of the blood-brain barrier in patients with gliomas

Friday, November 18, 2022

7:30 PM – 9:30 PM ET

Location: West/Central Hall

Poster Presenter(s)

Carlos G. Romo, MD

Johns Hopkins University School of Medicine
Baltimore, United States

Author(s)

Benjamin M. Ellingson, PhD

University of California Los Angeles
Los Angeles, United States
Roy Strowd, MD, MEd, MS (he/him/his)

Wake Forest University School of Medicine, Neuro-Oncology
Winston-Salem, United States
Glenn J. Lesser, MD

Wake Forest SOM
Winston Salem, United States
CR

Catalina Raymond, MS

University of California Los Angeles
Los Angeles, United States
BK

Brian Kral, MD

Johns Hopkins University School of Medicine
Baltimore, United States
XY

Xiaobu Ye, MD, MS

Johns Hopkins University School of Medicine
Baltimore, United States
SD

Serena Desideri, MD, inf., PhD

Johns Hopkins University School of Medicine
Baltimore, United States
JF

Joy Fisher, n/a

Johns Hopkins University School of Medicine
Baltimore, United States
Stuart A. Grossman, MD

Johns Hopkins University School of Medicine
Baltimore, United States

Background: The blood brain barrier (BBB) is a major obstacle to the delivery of chemotherapy to the CNS. Regadenoson is an FDA approved adenosine A2 agonist used for cardiac stress tests. In murine models, it transiently increases BBB permeability to a 70KD dextran. This multi-institutional, NIH funded, Adult Brain Tumor Consortium trial was designed to discover a dose of regadenoson that substantially increases vascular permeability in normal appearing white matter (NAWM) where drug delivery is particularly challenging.

Methods: Adults ages 18-45 with supratentorial gliomas at low-risk for regadenoson complications were recruited (n = 7). One patient was treated at each of seven dose levels (from 0.05 to 1.4 mg) that are known to be safe in humans. The primary outcome measure is change in vascular permeability via dynamic contrast enhanced (DCE) perfusion MRI estimates of K^trans. The primary outcome measure was a 10-fold higher K^trans in NAWM than reported in literature (K^trans > 0.04 min^-1). Contrast-enhanced T1 subtraction map estimates of change in contrast enhancement and other measurements in normal brain and non-enhancing tumor were quantified.

Results: K^trans measures in NAWM averaged 1.13x10^-3 ± 0.44x10^-3 (SEM) min^-1, lower than the target of 0.04 min^-1. Normalized, contrast enhanced T1-weighted MR signal intensity in NAWM increased an average of 74.0 ± 22.4% min^-1 (SEM) min^-1, which was significantly higher than zero (P = 0.0163). Data available from this limited sample failed to meet the target goal in K^trans increase or change in contrast enhancing signal intensity.

Conclusion: Administration of regadenoson at seven different doses did not significantly elevate K^trans for gadolinium in NAWM. This data suggests that single doses of regadenoson are unlikely to substantially increase the delivery of therapeutic agents in non-enhancing brain tissue. This trial design is appropriate for further human testing of other regadenoson schedules and other novel approaches aimed at transiently modifying BBB permeability.