Concurrent whole brain radiotherapy and RRx-001 for melanoma brain metastases

We report dramatic partial responses of 2 patients with melanoma brain metastases treated with the experimental radiosensitizer RRx-001, at the lowest dose of 5 mg/m², and whole brain radiotherapy (WBRT) in the context of a dose escalation phase I/II trial acronymed BRAINSTORM (NCT 02215512) at the University of Michigan. These partial responses occurred in the absence of any systemic or neurologic toxicity.

RRx-001 is a novel radiosensitizer, sourced from the aerospace industry, with epigenetic and immunostimulatory properties currently under investigation in multiple phase II trials. The first-in-man phase I results of single-agent RRx-001 were recently published in the September 2015 issue of The Lancet Oncology.¹ Preliminary clinical data with dynamic contrast enhanced MRI in the BRAINSTORM trial demonstrate a decrease in tumor vascular permeability with administration of RRx-001, suggestive of blood flow normalization, which in turn leads to increased oxygen delivery. The increase in tumor oxygenation results in enhanced reactive oxygen species formation in response to ionizing radiation, leading to radiation sensitization.

Historically, melanoma is considered to be a radioresistant tumor, with poor response rates in the setting of low-dose WBRT.² No significant advancements in the treatment of multiple brain metastases have occurred in the last few decades, and to date, no candidate radiosensitizers have emerged that have conclusively improved outcomes in patients with brain metastases. Although immunotherapies and targeted therapies have improved systemic disease outcomes in patients with melanoma, up to 40% of patients develop clinically detectable brain metastases, from which the majority die from uncontrolled intracranial disease.³ Figure 1 presents the results of 2 brain MRIs demonstrating confirmed partial responses in 2 patients at 1 month, 3 months, and 4 months with progressive shrinkage of the lesions over time.

Fig. 1.

(A) Left panel is a representative axial image from a T1 gadolinium-enhanced brain MRI of the patient's most symptomatic left occipital lesion prior to treatment. Middle panel demonstrates marked response of the lesion 1 month after 2 weeks of WBRT plus RRx-001, which was accompanied by resolution of the visual field deficits. Right panel demonstrates further response of the lesion 4 months after WBRT plus RRx-001. (B) Left panel is a representative image from a T1 gadolinium-enhanced brain MRI demonstrating a subcentimeter enhancing brain metastasis prior to treatment. Middle panel demonstrates the appearance of the lesion 1 month after the end of WBRT + RRx-001, which is not significantly changed in size. Right panel demonstrates complete disappearance of the lesion 4 months after the end of treatment.

Based on blood perfusion and vascular permeability parameters derived from dynamic contrast enhanced MRI with single-agent RRx-001 in this trial, a plausible mechanism of radiosensitization is increased blood flow and improved oxygenation as well as decrease in the tumor oxygen consumption rate (inhibition of respiration) that is mediated by a local production of nitric oxide by RRx-001–modified red blood cells, since RRx-001 binds covalently to hemoglobin.

This is the first in-human report demonstrating early evidence of safety and efficacy of RRx-001 in combination with WBRT in the first 2 patients with adequate follow-up treated on a phase I/II clinical trial. Because of the unique, unexpected early response demonstrated in this radioresistant histology, and because no prospective randomized trials have been conducted to assess the efficacy of WBRT in the melanoma patient population, RRx-001 administration may be a mechanism to improve tumor oxygenation and increase response to radiotherapy.

Funding

The authors disclose that the clinical trial in which these cases were observed is funded by EpicentRx, Inc. Authors Jan Scicinski and Bryan Oronsky are officers at EpicentRx, Inc.

Conflict of interest statement. None declared.