BRAINSTORM: A Multi-Institutional Phase I/II Study of RRx-001 in Combination with Whole Brain Radiation Therapy for Patients with Brain Metastases

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International journal of radiation oncology, biology, physics


BACKGROUND: To determine the RP2D 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 MRI after RRx-001 correlate with response.

METHODS: Five centers participated in this phase I/II trial of RRx-001 given once pre-WBRT 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 TITE-CRM algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability) and Vp (plasma volume) with change in tumor volume.

RESULTS: Between 2015-2017, 31 patients were enrolled. Two patients dropped out prior to 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 DLT's were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2/29). The median intracranial response rate was 46% (95%CI 24-68) and median OS was 5.2 months (95%CI 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing DCE-MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (p≤0.01).

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 RP2D is 10 mg twice weekly. A reduction in Vp by DCE-MRI 24 hours after RRx-001 suggests anti-angiogenic activity associated with longer-term tumor response.

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ePub ahead of print