BMX-001 as a Therapeutic Agent for Treatment of Multiple Brain Metastases.

PROJECT SUMMARY ABSTRACT In the United States an estimatedmillion patients will be newly diagnosed with cancer inand approximatelyof these patients will develop brain metastasesThe most common treatment for brain metastases is whole brain radiation therapyWBRTThe primary limitation to WBRT is neurotoxicityincluding brain white matter damagecognitive impairment and quality of life impairmentBMXis a new class of pharmaceuticalmetalloporphyrinthat in preclinical studies has been shown to provide marked protection against radiation induced tissue damage and at the same time to augment tumor growth inhibitionBMXis redox activescavenges reactive oxygen species and inhibits transcriptional activity of key inflammation related nuclear transcription factors such as NFKB and HIFIn animal models BMXhas been shown to prevent hippocampal stem cell loss and white matter degradation after WBRTBMXis currently in a Phaseclinical trial of patients with high grade glioma undergoing primary chemoradiation therapyNo adverse drug related events have identifiedand the Phasedose escalation trial will be completed by Decemberwith identification of a maximum tolerated doseMTDthat can be used for a Phaseclinical trialChemoradiation of high grade glioma involves localized brain radiation therapyIn contrastpatients with multiple brain metastasesMBMreceive whole brain irradiation under a different dose and protocol and have a somewhat different toxicity profileThis proposed fast track SBIR will support a Phasesafety lead in clinical trial of BMXin combination with WBRT inpatients with MBMThe dose will be the MTD selected from the current clinical trial of patients with high grade glioma undergoing brain chemoradiation therapyDemonstrating safety of the selected MTD of BMXin patients with MBM undergoing standard protocol WBRT will be thego no gocriteria for proceeding to Phase II of this SBIRPhase II will be a randomized open label Phaseclinical trial ofpatients with MBMhalf receiving BMXin combination with WBRT and half receiving WBRT aloneThe hypothesis being tested is that BMXis an effective radioprotector in WBRT of patients with MBM from extracranial primary tumorsThe primary proposed outcome is protection improvement of cognitionSecondary outcomes areefficacy based on overall and progression free survivalmedian distant brain new metastases rateandrate of death from neurologic causesExploratory outcomes arequality of life andhair lossThe proposed randomizedpatient trial will provide essential data on the efficacy of BMXin modifying the neurotoxicity of WBRT and will enable design and implementation of future expanded trials with sufficient power to demonstrate drug efficacy and move this new class of pharmaceuticals toward appropriate commercialization PROJECT NARRATIVE This fast track SBIR will support a lead in safety study and a randomized Phaseclinical trial of BMXa new class of pharmaceuticalin patients with multiple brain metastases undergoing whole brain radiation therapyPreliminary studies have demonstrated that BMXprovides protection of normal tissues from radiation induced injury and augments tumor growth inhibitionThe proposed trial will test the hypothesis that BMXis an effective radioprotector in patients with brain metastases undergoing whole brain radiation therapy