Courtney D. DiNardo, Divij Verma, Natalia Baran, Tushar D. Bhagat, Anna Skwarska, Alessia Lodi, Kapil Saxena, Tianyu Cai, Xiaoping Su, Veronica A. Guerra, Gowri Poigaialwar, Vinitha M. Kuruvilla, Sergej Konoplev, Shanisha Gordon-Mitchell, Kith Pradhan, Srinivas Aluri, G. Lavender Hackman, Sovira Chaudhry, Meghan Collins, Shannon R. Sweeney, Jonathan Busquets, Atul Singh Rathore, Qing Deng, Michael R. Green, Steven Grant, Susan Demo, Gaurav S. Choudhary, Srabani Sahu, Beamon Agarwal, Mason Spodek, Victor Thiruthuvanathan, Britta Will, Ulrich Steidl, George D. Tippett, Jan Burger, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Tapan Kadia, Steven Kornblau, Naval G. Daver, Kiran Naqvi, Nicholas J. Short, Guillermo Garcia-Manero, Stefano Tiziani, Amit Verma, Marina Konopleva
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引用次数: 0
Abstract
Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 . DiNardo et al. perform a phase 1b/2 clinical trial of telaglenastat (CB-839) in combination with azacytidine in persons with advanced myelodysplastic syndromes and report on the treatment safety and efficacy, including a definition of clinical responders.
期刊介绍:
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