A randomized, proof-of-concept, Phase 2 clinical trial of a new class of redox-active pharmaceutical is proposed in 160 subjects undergoing primary treatment for high-grade glioma (WHO grade III and IV). Under a prior Phase II SBIR, a Phase 1 clinical trial has been completed with establishment of the recommended dose being used for this Phase 2 clinical trial. This project will test a compound that, in animals, has been demonstrated to cross the blood-brain barrier and prevent hippocampal stem cell loss and white matter degradation following radiation therapy (RT). The compound also enhances tumor killing in combination with radiation therapy and thus has the dual impact of protecting normal tissues while improving tumor treatment responses. This drug is both neuroprotective against RT and is expected to enhance inhibition of glioblastoma by RT. Primary brain tumors represent 1% of all diagnosed cancers. Even though these tumors represent a rare malignancy, high-grade gliomas are aggressive and lethal and are associated with severe disabling central nervous system involvement. Cognition and neurological function are compromised at diagnosis and during treatment. The standard of care for newly diagnosed high-grade gliomas involves surgical resection, followed by RT with concurrent temozolomide (TMZ). Despite aggressive treatment, nearly all patients with the most common form of adult primary brain tumor, glioblastoma (WHO grade IV), die of disease progression; median survival is 12-16 months after diagnosis. Most high-grade gliomas are resistant to current available therapies. Thus, a major require- ment for the next generation therapy of primary brain tumors is more effective tumor control, protection against neurotoxicity, and reduction in the incidence of bone marrow suppression (i.e., thrombo- cytopenia). The Phase 2 clinical trial proposed in this SBIR Phase IIB Bridge Award is to test the hypothesis that BMX-001, the lead compound in a new class of redox-active metalloporphyrins, will extend patient survival and at the same time protect normal tissues and enhance quality of life.
The specific aims are to: 1) confirm enhanced survival (tumor control) by completing a randomized, open- label Phase 2 clinical trial of BMX-001 in combination with standard RT and TMZ in newly diagnosed high-grade glioma patients (160 subjects, 1:1 randomization), and 2) confirm protection from side effects of radiochemotherapy by assessing cognition, white matter integrity, quality of life (HRQoL) and bone marrow protection. The primary outcomes are 1) Efficacy based on overall and progression-free survival; 2) Protection/improvement of cognition; 3) Radiographic response of tumor; and 4) Protection of bone marrow against chemotherapy-induced thrombocytopenia. Exploratory outcomes are 1) HRQoL and 2) White matter integrity (MRI brain diffusion tensor imaging).
A randomized Phase 2 clinical trial of a new class of redox-active pharmaceutical is proposed in 160 subjects with high-grade glioma (HGG) under primary radiation and chemotherapy. This new class of drug has the potential to enable more effective tumor control as demonstrated by overall and progression- free survival and radiographic assessment of tumor growth. At the same time, this new class of drug is postulated to protect against deterioration of cognition, protect bone marrow against chemotherapy- induced thrombocytopenia, and improve health-related quality of life (HRQoL).
