PMID- 36709310 OWN - NLM STAT- MEDLINE DCOM- 20230131 LR - 20230202 IS - 1868-7083 (Electronic) IS - 1868-7075 (Print) IS - 1868-7075 (Linking) VI - 15 IP - 1 DP - 2023 Jan 28 TI - A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma. PG - 15 LID - 10.1186/s13148-023-01427-7 [doi] LID - 15 AB - BACKGROUND: N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR-MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity. RESULTS: Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1-20). Grade 3-4 adverse events (AEs) were reported in seven (54%; 95% CI 25-81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0-36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29-539) days and 33 (95% CI 9.7- > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39-91%). PK analysis demonstrated proportional dose-concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months. CONCLUSIONS: NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR-MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention. CI - (c) 2023. The Author(s). FAU - Jake Shortt AU - Jake Shortt AD - Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia. jake.shortt@monash.edu. AD - Monash Haematology, Monash Health, Clayton, VIC, Australia. jake.shortt@monash.edu. AD - Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia. jake.shortt@monash.edu. FAU - Galettis, Peter AU - Galettis P AD - Centre for Drug Repurposing and Medicines Research, University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, Kookaburra Circuit, New Lambton Heights, NSW, Australia. FAU - Cheah, Chan Y AU - Cheah CY AD - Department of Haematology, Sir Charles Gairdner Hospital, Perth, WA, Australia. AD - Division of Internal Medicine, Medical School, University of Western Australia, Perth, WA, Australia. FAU - Davis, Joanne AU - Davis J AD - ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia. AD - Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. FAU - Ludford-Menting, Mandy AU - Ludford-Menting M AD - ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia. AD - Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. FAU - Link, Emma K AU - Link EK AD - Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia. AD - Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. FAU - Martin, Jennifer H AU - Martin JH AD - Centre for Drug Repurposing and Medicines Research, University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, Kookaburra Circuit, New Lambton Heights, NSW, Australia. FAU - Koldej, Rachel AU - Koldej R AD - ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia. AD - Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. FAU - Ritchie, David AU - Ritchie D AD - ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia. david.ritchie@mh.org.au. AD - Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. david.ritchie@mh.org.au. AD - Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia. david.ritchie@mh.org.au. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230128 PL - Germany TA - Clin Epigenetics JT - Clinical epigenetics JID - 101516977 RN - JR9CE63FPM (N-methylpyrrolidone) RN - 0 (Nuclear Proteins) RN - 0 (Transcription Factors) SB - IM MH - Humans MH - *Multiple Myeloma/drug therapy MH - Nuclear Proteins MH - Transcription Factors MH - DNA Methylation MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use PMC - PMC9884426 OTO - NOTNLM OT - Bromodomain OT - Immunomodulation OT - Multiple myeloma OT - N-methyl-2-pyrrolidone COIS- JS and DR are inventors on patent WO2011160170A1 'stimulating immune response'. There are no other competing interests related to the published work. EDAT- 2023/01/29 06:00 MHDA- 2023/02/01 06:00 PMCR- 2023/01/28 CRDT- 2023/01/28 23:31 PHST- 2022/09/25 00:00 [received] PHST- 2023/01/13 00:00 [accepted] PHST- 2023/01/28 23:31 [entrez] PHST- 2023/01/29 06:00 [pubmed] PHST- 2023/02/01 06:00 [medline] PHST- 2023/01/28 00:00 [pmc-release] AID - 10.1186/s13148-023-01427-7 [pii] AID - 1427 [pii] AID - 10.1186/s13148-023-01427-7 [doi] PST - epublish SO - Clin Epigenetics. 2023 Jan 28;15(1):15. doi: 10.1186/s13148-023-01427-7.