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.
Figure 1 Figure 1.
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 advisory 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
Assembly of the [4Fe–4S] cluster of NFU1 requires the coordinated donation of two [2Fe–2S] clusters from the scaffold proteins, ISCU2 and ISCA1