Preserving Neurocognition Without Compromising Tumor Control During Whole-Brain Radiotherapy Therapy In Patients With Numerous Brain Metastases Via A Novel Superoxide Dismutase Mimetic: Initial Safety Lead-In And Design Of A Clinical Trial

Abstract

Patients with a large number of brain metastases (BM) present a clinical challenge. While stereotactic radiosurgery (SRS) has 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. 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, even with hippocampal avoidance, altered fractionation and neuroprotectants. 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. We hypothesized that this agent would reduce neurocognitive decline while possibly improving tumor control in patients with numerous brain metastases undergoing WBRT. This protocol is composed of a lead-in safety study of 5 patients followed by a randomized Phase 2 clinical trial of BMX-001, in 64 patients with multiple brain metastases (MBM) undergoing WBRT. Eligible patients are adults with more than 10 brain metastases, a KPS of >60 and a life expectancy >3 months. All patients will undergo WBRT to a total dose of 30 Gy in 3 Gy daily fractions. Patients in the safety lead-in study and the BMX-001 cohort of the randomized trial will receive a loading dose of this agent immediately prior to starting WBRT, then a maintenance dose twice weekly during WBRT and once within 4 days of completing WBRT. Primary endpoint is change in neurocognition, as measured by Trailmaking, Hopkins Verbal Learning and Controlled Oral Word Association tests pre and post WBRT. Secondary endpoints include overall survival, quality of life, toxicity, local recurrence, distant brain failure, neurologic death and radionecrosis. The safety lead-in portion of this trial was completed in August 2019. All 5 patients completed WBRT and BMX-001 per protocol. The majority of subjects experienced Grade 1 non-hematologic AEs, primarily injection site reactions (including erythema, itching, welts, bruising around injection sites); 1 patient experienced a Grade 2 QT prolongation. No severe toxicities (Grade 3), life-threatening toxicities (Grade 4), or treatment related deaths (Grade 5) were reported. Initial post-WBRT brain MR imaging showed at least a partial tumor response. The randomized clinical trial is now open at multiple institutions. It appears reasonable to proceed with the randomized clinical trial of WBRT +/- BMX-001 in patients with numerous brain metastases. Enrollment on this trial is essential to test the hypothesis that this agent is an effective neuroprotectant.