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
ABSTRACT
Introduction: Patients (pts) with primary refractory or relapsed Burkitt lymphoma/leukemia (BL) or high-grade B-cell lymphoma with MYC and BCL2 rearrangements (double hit, DHL) and/or BCL6 (triple hit, THL) have a dismal prognosis. A dysregulated MYC oncogene has downstream effects on proliferation and highly glycolytic metabolism with tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. Devimistat is a non-redox active analogue of lipoic acid, a required cofactor for two key TCA cycle mitochondrial enzymes: pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption results in a shutdown of ATP and biosyntheticintermediate production leading to cancer cell death. In a phase I trial (n = 26) a pt with multiply refractory BL had a partial remission sustained over one year prior to resection. She remains in remission 7 years later. As of March 2021, 20 clinical studies in over 700 pts with various cancers have been conducted (ongoing/completed) with devimistat. We initiated a phase II trial to further explore efficacy. Methods: NCT03793140 is a multicenter study enrolling 17 patients on each of two cohorts BL or DHL/THL. Pts must have had one prior therapy or are refusing standard of care, measurable disease or isolated bone marrow involvement, and must not be within 3 months of a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks and the maintenance intrathecal/intraOmmaya 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 every 21 days. Pts are evaluable for response if they receive at least 4/5 days of the first cycle. At least 1response in the first 9 pts by cycle 3 was needed to expand to 17 pts in total in that cohort. Results: 9 pts were enrolled in the DHL/THL arm. Number of prior therapies was 3(1-6). No responses and only 1 stable disease resulted in cohort closure. Thus far, 8 BL pts were enrolled. Number of prior therapies was 3 (2-4). 2 pts were inevaluable. 1/6 pts had a response. This HIV+ pt had a thigh mass having received 4 prior therapies. He had a near complete metabolic remission after 3 cycles of devimistat. PET/CT assessment: Thigh lesion baseline October 19, 2020: 10.8 x 6.5 cm SUV 24. After cycle 3: unmeasurable, SUV 2. He is currently in cycle 7, 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 March 03, 2021, no serious AEs related to study drug. 4 pts 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 near complete remission in this patient is promising in a disease where no viable treatment options exist.