TRLS-10. MITIGATING NEUROCOGNITIVE DEFICITS FROM WHOLE-BRAIN RADIOTHERAPY IN PATIENTS WITH NUMEROUS BRAIN METASTASES VIA A NOVEL SUPEROXIDE DISMUTASE MIMETIC: RATIONALE & DESIGN OF A CLINICAL TRIAL

BACKGROUND: Patients with a large number of brain metastases (BM) and/or micrometastatic disease in the brain present a clinical challenge. While technical innovations in stereotactic radiosurgery (SRS) have extended the number of BM that can be effectively treated, SRS does not treat occult disease and distant brain failure (DBF) post-SRS remains high. Immuno- and targeted therapies show promise in treating metastatic disease to the brain, though response rates are variable. In contrast, whole-brain radiotherapy (WBRT) provides high rates of local control and, compared to SRS, reduces the risk of distant brain failure. Unfortunately, WBRT is also associated with substantial neurocognitive deficits and neither altered fractionation nor the use of available neuroprotectants has adequately addressed this issue. An agent that safely minimizes the adverse effects of WBRT while preserving or enhancing tumor control would provide meaningful clinical benefit. TRIAL DESIGN: BMX-001, a novel Mn-porphyrin superoxide dismutase mimetic, has been shown to protect normal tissues from ionizing radiation in preclinical trials, reducing neurocognitive adverse effects as well as enhancing tumor response. Based on the first-in-human trial of this agent in patients with high-grade gliomas, we have instituted a clinical trial of WBRT +/- BMX-001 in adult patients with more than 10 BM from melanoma, non-small-cell lung, breast and renal cancer. Following a safety lead-in of 5 patients, all of whom will receive WBRT and BMX-001, 69 patients will be randomized to WBRT (3Gy/fraction x 10 fractions) with or without BMX-001 administered subcutaneously before, twice weekly during and once after WBRT (6 injections total.) The primary endpoint is cognition, as measured by the Hopkins Verbal Learning, Trailmaking A/B and Controlled Oral Word Association tests. Secondary endpoints include health-related quality-of-life, overall and progression-free survival, rates of radiation necrosis, DBF and neurologic death. Enrollment began January 2019. (ClinicalTrials.gov Identifier: NCT03608020.)