In the United States an estimated 1.7 million patients will be newly diagnosed with cancer in 2017 and approximately 15% of these patients will develop brain metastases. The most common treatment for brain metastases is whole brain radiation therapy (WBRT). The primary limitation to WBRT is neurotoxicity, including brain white matter damage, cognitive impairment and quality of life impairment. BMX-001 is a new class of pharmaceutical (metalloporphyrin) that in preclinical studies has been shown to provide marked protection against radiation-induced tissue damage and at the same time to augment tumor growth inhibition. BMX-001 is redox-active, scavenges reactive oxygen species and inhibits transcriptional activity of key inflammation-related nuclear transcription factors such as NFKB and HIF-1. In animal models BMX-001 has been shown to prevent hippocampal stem cell loss and white matter degradation after WBRT. BMX-001 is currently in a Phase 1 clinical trial of patients with high-grade glioma undergoing primary chemoradiation therapy. No adverse drug-related events have identified, and the Phase 1 dose escalation trial will be completed by December 2017 with identification of a maximum tolerated dose (MTD) that can be used for a Phase 2 clinical trial. Chemoradiation of high-grade glioma involves localized brain radiation therapy. In contrast, patients with multiple brain metastases (MBM) receive whole brain irradiation under a different dose and protocol and have a somewhat different toxicity profile. This proposed fast-track SBIR will support a Phase 1 safety lead-in clinical trial of BMX-001 in combination with WBRT in 5 patients with MBM. The dose will be the MTD selected from the current clinical trial of patients with high-grade glioma undergoing brain chemoradiation therapy. Demonstrating safety of the selected MTD of BMX-001 in patients with MBM undergoing standard protocol WBRT will be the ?go/no-go? criteria for proceeding to Phase II of this SBIR. Phase II will be a randomized open-label Phase 2 clinical trial of 50 patients with MBM, half receiving BMX-001 in combination with WBRT and half receiving WBRT alone. The hypothesis being tested is that BMX-001 is an effective radioprotector in WBRT of patients with MBM from extracranial primary tumors. The primary proposed outcome is protection/improvement of cognition. Secondary outcomes are 1) efficacy based on overall and progression-free survival, 2) median distant brain new metastases rate, and 3) rate of death from neurologic causes. Exploratory outcomes are 1) quality of life and 2) hair loss. The proposed randomized 50-patient trial will provide essential data on the efficacy of BMX-001 in 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.
This fast-track SBIR will support a lead-in safety study and a randomized Phase 2 clinical trial of BMX- 001, a new class of pharmaceutical, in patients with multiple brain metastases undergoing whole brain radiation therapy. Preliminary studies have demonstrated that BMX-001 provides protection of normal tissues from radiation-induced injury and augments tumor growth inhibition. The proposed trial will test the hypothesis that BMX-001 is an effective radioprotector in patients with brain metastases undergoing whole brain radiation therapy.