BRAINSTORM: A Multi-Institutional Phase I/II Study of RRx-001 in Combination with Whole Brain Radiation Therapy for Patients with Brain Metastases.
Kim MM, Parmar HA, Schipper M, Devasia T, Aryal MP, Kesari S, O'Day S, Morikawa A, Spratt DE, Junck L, Mammoser A, Hayman JA, Lawrence TS, Tsien CI, Aiken R, Goyal S, Abrouk N, Trimble M, Cao Y, and Lao CD. BRAINSTORM: A Multi-Institutional Phase I/II Study of RRx-001 in Combination with Whole Brain Radiation Therapy for Patients with Brain Metastases. Int J Radiat Oncol Biol Phys 2020.
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.
ePub ahead of print