A Phase II Clinical Trial of Cpi-613 (devimistat) in Patients with Relapsed or Refractory Burkitt Lymphoma/Leukemia or High-Grade B-Cell Lymphoma with Rearrangements of MYCand BCL2 and/orBCL6

Background:Patients with primary refractory or relapsed Burkitt lymphoma/leukemia (BL) or high-grade B-cell lymphoma with rearrangements of MYCand BCL2(double hit, DHL) and/orBCL6 (triple hit, THL) have a dismal prognosis with patients rarely achieving meaningful remissions following second line therapy. No standard therapeutic approach exists for this group. The characteristic hallmark of these diseases is a dysregulated MYConcogene with downstream effects on both proliferation and highly glycolytic metabolism which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI 613® (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle: pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of these enzyme activities results in a shutdown of ATP and biosynthetic-intermediate production leading to cancer cell death by apoptosis or necrosis. In the initialphase I trial a patient with multiply refractory BL had a partial remission on CPI 613 sustained for over one year prior to surgical resection. Given the rarity of these types of responses in multiply relapsed BL we initiated a phase II trial to further explore efficacy. CPI-613® has FDA orphan status for BL.