BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases

Authors

Michelle M. Kim, University of Michigan, Ann Arbor
Hemant A. Parmar, University of Michigan, Ann Arbor
Matthew Schipper, University of Michigan, Ann Arbor
Theresa Devasia, University of Michigan, Ann Arbor
Madhava P. Aryal, University of Michigan, Ann Arbor
Santosh Kesari, John Wayne Cancer Institute
Steven O'Day, John Wayne Cancer Institute
Aki Morikawa, University of Michigan, Ann Arbor
Daniel E. Spratt, University of Michigan, Ann Arbor
Larry Junck, University of Michigan, Ann Arbor
Aaron Mammoser, Louisiana State University
James A. Hayman, University of Michigan, Ann Arbor
Theodore S. Lawrence, University of Michigan, Ann Arbor
Christina I. Tsien, Washington University School of Medicine in St. Louis
Robert Aiken, Rutgers Cancer Institute of New Jersey
Sharad Goyal, The George Washington University
Nacer Abrouk, Clinical Trials Innovations
Malcolm Trimble, Henry Ford Allegiance Health
Yue Cao, University of Michigan, Ann Arbor
Christopher D. Lao, University of Michigan, Ann Arbor

Document Type

Journal Article

Publication Date

7-1-2020

Journal

International Journal of Radiation Oncology Biology Physics

Volume

107

Issue

3

DOI

10.1016/j.ijrobp.2020.02.639

Abstract

© 2020 The Author(s) Purpose: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. Methods and Materials: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. Results: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤.01). Conclusions: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response.

APA Citation

Kim, M., Parmar, H., Schipper, M., Devasia, T., Aryal, M., Kesari, S., O'Day, S., Morikawa, A., Spratt, D., Junck, L., Mammoser, A., Hayman, J., Lawrence, T., Tsien, C., Aiken, R., Goyal, S., Abrouk, N., Trimble, M., Cao, Y., & Lao, C. (2020). BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases. International Journal of Radiation Oncology Biology Physics, 107 (3). http://dx.doi.org/10.1016/j.ijrobp.2020.02.639