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

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

Phase II Study of Pembrolizumab Plus GVD As Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma

Introduction: The standard approach for relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) following front-line treatment failure is second line therapy (SLT) aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). No one standard SLT exists and options include regimens containing platinum, gemcitabine, and more recently brentuximab vedotin (BV). Complete response rates associated with these regimens range from 50-70%. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. Programmed death-1 (PD-1) inhibitors are highly active in RR cHL and have the potential to enhance the efficacy of standard chemotherapy. Here we report the results of our phase II study evaluating a novel anti-PD-1-based regimen, pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD), as SLT for RR cHL. Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Pts who achieved CR by PET (Deauville ≤3) after 2 or 4 cycles proceeded to HDT/AHCT. HDT/AHCT was carried out according to institutional standards and BV maintenance was allowed following HDT/AHCT. The primary endpoint was CR rate after 2 or 4 cycles of pembrolizumab-GVD. Enrollment occurred according to a Simon 2-stage design with sample size based upon a projected CR rate of 70%. In stage 1, 23 pts enrolled and 12 or more CRs were required to proceed to stage II;in stage II, an additional 16 pts enrolled. Out of a total of 39 pts, 24 CRs were required to declare this regimen promising. Results: Among 39 patients enrolled, 37 are evaluable for toxicity (2 pts have not yet started treatment) and 34 are evaluable for response (4 pts too early, 1 pt found to have composite lymphoma after enrollment). Of 37 treated pts, median age is 36 (range 21-71), 43% are male, 23 (62%) had advanced stage disease, and 15 (41%) had primary refractory disease. With regard to RR cHL risk factors (B-symptoms, extranodal disease, and relapse/refractory disease within 1 year of initial treatment), 4(11%) had no risk factors (RFs), 21 (57%) had 1 RF, 9 (24%) had 2 RFs, and 3 (8%) had all 3 RFs. Treatment was well tolerated with most adverse events being grade 1 or 2 (see figure 1). Grade 3 AEs included rash (n=1), elevated AST/ALT (n=3), oral mucositis (n=2), and neutropenia (n=3). Figure 2 shows the outcome for all 37 treated pts. Among 34 evaluable pts, 31 (91%) achieved CR after 2 cycles and 3 achieved partial response. An additional 1 pt achieved CR after 4 cycles of pembrolizumab-GVD, therefore in total, 32 of 34 (94%) achieved CR following pembrolizumab-GVD. 4 pts with CR after 2 cycles received an additional 2 cycles of pembrolizumab-GVD in order to delay HDT/AHCT during the height of the COVID-19 pandemic (n=3) or due to refusing HDT/ASCT (n=1). To date, 32 have undergone HDT/AHCT following 2 (n=27) or 4 (n=5) cycles of treatment. 1 pt is awaiting HDT/AHCT;1 pt refused HDT/ASCT and received pembrolizumab maintenance instead. 2 pts received involved site radiation therapy to initial area of relapsed disease prior to planned HDT/AHCT and 10 pts received post-HDT/ASCT maintenance with BV. Median follow-up post-HDT/AHCT is 9 mos (range 0.03-20.9 mos) and all pts remain in remission to date. Conclusion: Second-line therapy with pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/AHCT. Updated results including all 39 enrolled pts will be presented at the meeting. Given the high CR rate observed with pembrolizumab-GVD, an expansion cohort evaluating 8 cycles of pembrolizumab maintenance (instead of HDT/AHCT) for patients who achieve CR af er 4 cycles of pembrolizumab-GVD is planned. [Formula presented] Disclosures: Moskowitz: Merck: Consultancy;Incyte: Research Funding;Miragen Therapeutics: Consultancy;Seattle Genetics: Consultancy;Imbrium Therapeutics, L.P.: Consultancy;Merck: Research Funding;Seattle Genetics: Research Funding;Bristol-Myers Squibb: Research Funding. Shah: Amgen Inc.: Research Funding;Janssen: Research Funding. Kumar: AbbVie: Research Funding;Celgene: Honoraria, Other: Honoraria for Advisory Board;Seattle Genetics: Research Funding;Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board;Celgene: Research Funding;Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board;Adaptive Biotechnologies,: Research Funding;Pharmacyclics: Research Funding. Lahoud: MorphoSys: Other: Advisory Board. Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy;Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Hamlin: J&J Pharmaceuticals: Research Funding;Portola: Research Funding;Incyte: Research Funding;Portola Pharmaceutics: Consultancy;Juno Therapeutics: Consultancy;Karyopharm: Consultancy;Celgene: Consultancy;Molecular Templates: Research Funding. Straus: Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees;Imedex, Inc.: Speakers Bureau;Targeted Oncology: Consultancy, Speakers Bureau;NY Lymphoma Rounds: Consultancy;Takeda Pharmaceuticals: Research Funding, Speakers Bureau;OncLive: Speakers Bureau;Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer;ASH: Other: Conference in December 2019 on HL to other physicians during ASH;Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz: ASTEX: Consultancy;Verastem: Consultancy, Research Funding;Myeloid Therapeutics: Consultancy;Miragen: Consultancy;Kura Oncology: Consultancy;Janssen: Consultancy;GlaxoSmithKline: Consultancy;Daiichi Sankyo: Research Funding;C4 Therapeutics: Consultancy;Affirmed: Consultancy;Vividion Therapeutics: Consultancy;Beigene: Consultancy;Portola: Consultancy, Research Funding;Mundipharma: Consultancy;Innate Pharma: Consultancy;Corvus: Consultancy;Trillium: Consultancy, Research Funding;Seattle Genetics: Consultancy, Research Funding;Millenium/Takeda: Consultancy, Research Funding;Kyowa Hakka Kirin: Consultancy, Research Funding;Infinity/Verastem: Research Funding;Forty Seven: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Aileron: Consultancy, Research Funding;ADCT Therapeutics: Consultancy, Research Funding. Falchi: Genmab: Research Funding;Roche: Research Funding. Joffe: Epizyme: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Noy: Pharmacyclics: Research Funding;Pharmacyclics: Consultancy;Janssen: Consultancy;Rafael Pharma: Research Funding;NIH: Research Funding;Morphosys: Consultancy;Medscape: Consultancy;Targeted Oncology: Consultancy. Matasar: Teva: Consultancy;Genentech, Inc.: Consultancy, Honoraria, Research Funding;Merck: Consultancy;Bayer: Consultancy, Honoraria, Research Funding;Juno Therapeutics: Consultancy;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding;GlaxoSmithKline: Honoraria, Research Funding;IGM Biosciences: Research Funding;Janssen: Honoraria, Research Funding;Pharmacyclics: Honoraria, Research Funding;Immunovaccine Technologies: Honoraria, Research Funding;Rocket Medical: Consultancy, Research Funding;Takeda: Consultancy, Honoraria;Daiichi Sankyo: Consultancy;Seattle Genetics: Consultancy, Honoraria, Research Funding. Vardhana: Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell: Genentech: Research Funding;Bayer: Research Funding;Pharmacyclics: Research Funding. Zelenetz: Novartis: Consultancy;Janssen: Consultancy;Celge e: Consultancy;Amgen: Consultancy;Adaptive Biotechnology: Consultancy;BeiGene: Membership on an entity's Board of Directors or advisory committees;Roche: Research Funding;Gilead: Research Funding;Genentech/Roche: Consultancy;Gilead: Consultancy;Sandoz: Research Funding;Celgene: Research Funding;MEI Pharma: Research Funding;MorphoSys: Research Funding. OffLabel Disclosure: Pembrolizumab as second-line therapy for Hodgkin lymphoma

Preliminary activity of devimistat (CPI 613) in patients with relapsed or refractory burkitt lymphoma/leukemia

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.