Complete Remission with Devimistat (CPI-613) in Refractory Burkitt Lymphoma

ABSTRACT

Introduction: Patients (pts) with primary refractory or relapsed high-grade lymphoma (HGL) including Burkitt lymphoma (BL) and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphoma, DHL) have a dismal prognosis with patients almost never achieving a meaningful remission to second line therapy. No standard second line therapeutic approach exists, particularly for BL. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with both downstream effects on proliferation and a high metabolic fluxes 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 mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis. In the initial phase I trial (n=26) one patient with multiply refractory BL had a partial remission sustained for over one year and then consolidated by surgical resection. She remains alive 7 years later. As of July 2021, 20 clinical studies for various cancers have been conducted (ongoing/completed) with devimistat with over 700 patients having received study drug. We initiated a phase II trial to further explore efficacy in HGL. Devimistat has FDA orphan status for BL and 4 other cancers. Methods: NCT03793140 is a multicenter study aiming to enroll 17 patients on each of two cohorts, BL and DHL, with a Simon's 2-stage design for each cohort, requiring one response among the first 9 treated patients to expand to 17. Patients must have had at least one prior line of therapy or are refusing standard of care and must be more than 3 months after a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but prior leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks at enrollment and maintenance intrathecal therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance x5 days every 21 days. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle. Results: 9 pts were enrolled in the DHL/THL arm. Mediannumber of prior therapies were 3 (range, 1-6). No responses were seen, with only 1 patient achieving stable disease as best response, resulting in cohort closure. Thus far, 8 BL pts were enrolled. Median number of prior therapies was 3 (range, 2-4). Two patients were inevaluable for response. 1/6 patients had stable disease through cycle 7 and one had a complete response (CR). This CR patient (HIV+) with 4 prior therapies entered the study with only a biopsy proven thigh mass. He was not a transplant candidate for social reasons. He had a near complete metabolic remission after 4 cycles of devimistat and a CR after cycle 7. (Table and Figure) As of July 2021, he is in cycle 11, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE) As of July30, 2021, no patient experienced a serious adverse event related to study drug. Four patients had grade 3 events at least possibly related 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase. Conclusions: Although our results are preliminary, the complete remission in this patient is promising in a disease where no viable treatment options exist in the relapsed, refractory BL. Enrollment to the BL cohort is ongoing. [Formula presented] Disclosures Nikolaenko Pfizer Research Funding;Rafael Pharmaceuticals Research Funding. Pardee Celgene/BMS Consultancy, Speakers Bureau;Amgen Consultancy, Speakers Bureau;Pharmacyclics Consultancy, Speakers Bureau;Janssen Consultancy, Speakers Bureau;AbbVie Membership on an entity's Board of Directors or advisor committees;CBM Biopharma Membership on an entity's Board of Directors or advisory committees;Karyopharm Research Funding;Rafael Pharmaceuticals Research Funding. Abramson Genentech Consultancy;Kymera Consultancy;Karyopharm Consultancy;AbbVie Consultancy;Seagen Inc. Research Funding;Allogene Therapeutics Consultancy;Astra-Zeneca Consultancy;Incyte Corporation Consultancy;BeiGene Consultancy;Bluebird Bio Consultancy;Genmab Consultancy;EMD Serono Consultancy;Bristol-Myers Squibb Company Consultancy, Research Funding;C4 Therapeutics Consultancy;Morphosys Consultancy;Kite Pharma Consultancy;Novartis Consultancy. Horwitz Vividion Therapeutics Consultancy;Shoreline Biosciences, Inc. Consultancy;Tubulis Consultancy;Verastem Research Funding;ONO Pharmaceuticals Consultancy;Myeloid Therapeutics Consultancy;SecuraBio Consultancy, Research Funding;Trillium Therapeutics Consultancy, Research Funding;Seattle Genetics Consultancy, Research Funding;Millennium /Takeda Consultancy, Research Funding;Kura Oncology Consultancy;Janssen Consultancy;Kyowa Hakko Kirin Consultancy, Research Funding;Forty Seven, Inc. Research Funding;Daiichi Sankyo Research Funding;C4 Therapeutics Consultancy;Celgene Research Funding;Aileron Research Funding;Affimed Research Funding;Acrotech Biopharma Consultancy;ADC Therapeutics Consultancy, Research Funding. Matasar GlaxoSmithKline Honoraria, Research Funding;Teva Consultancy;Janssen Honoraria, Research Funding;Bayer Consultancy, Honoraria, Research Funding;Genentech, Inc. Consultancy, Honoraria, Research Funding;Merck Sharp & Dohme Current holder of individual stocks in a privately-held company;F. Hoffmann-La Roche Ltd Consultancy, Honoraria, Research Funding;IGM Biosciences Research Funding;Merck Consultancy;Juno Therapeutics Consultancy;TG Therapeutics Consultancy, Honoraria;Seattle Genetics Consultancy, Honoraria, Research Funding;Memorial Sloan Kettering Cancer Center Current Employment;Pharmacyclics Honoraria, Research Funding;Daiichi Sankyo Consultancy;ImmunoVaccine Technologies Consultancy, Honoraria, Research Funding;Takeda Consultancy, Honoraria;Rocket Medical Consultancy, Research Funding. Noy Rafael Parhma Research Funding;Morphosys Consultancy;Targeted Oncology Consultancy;Medscape Consultancy;Pharmacyclics Consultancy, Research Funding;Janssen Consultancy, Honoraria;Epizyme Consultancy. OffLabel Disclosure 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 mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis