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• W4297991528 abstract "Abstract 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 50–400mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1g 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 200mg 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 400mg daily, with a more linear relationship above 500mg. Maximum plasma concentrations (Cmax) of 16.7mg/L at the 800mg 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 1g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention." @default.
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• W4297991528 date "2022-09-29" @default.
• W4297991528 modified "2023-09-26" @default.
• W4297991528 title "A phase 1 clinical trial of the repurposable acetyl-lysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma" @default.
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• W4297991528 doi "https://doi.org/10.21203/rs.3.rs-2102432/v1" @default.
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