A phase I, open-label, study of GSK2879552, a lysine-specific demethylase 1 (LSD1) inhibitor, in patients with relapsed/refractory small cell lung carcinoma (SCLC)

  • Moreno V
  • Bauer T
  • Infante J
  • et al.
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Abstract

Background: SCLC is initially responsive to chemotherapy; however, patients ultimately relapse. Response to second-line therapy is poor with an overall survival of <6 months. LSD1 mediates transcriptional repression of target genes that regulate differentiation by removing mono- and dimethyl groups from methylated histone H3 at lysine 4. LSD1 is highly expressed in primary SCLC, and so may serve as a therapeutic target. GSK2879552, a selective and potent inhibitor of LSD1/CoRepressor for Element-1-Silencing Transcription factor (CoREST) activity, induces the expression of putative LSD1 target genes and demonstrates strong, predominantly cytostatic, antiproliferative activity in SCLC cell lines/ tumor xenograft models Methods: This is a Phase I, open-label, first-time-in-human, 2-part study. Part 1 is a dose escalation phase in patients (>18 years) with relapsed/refractory SCLC (after >1 platinum containing therapy) to determine the safety, tolerability and recommended Phase 2 dose (RP2D) of GSK2879552. Inclusion criteria include: ECOG PS of 0/1; histologically/cytologically confirmed diagnosis of SCLC. One patient will receive a starting dose of 0.25mg of GSK2879552 (orally) once-daily for 28 days, followed by a safety and pharmacokinetic data review, after which dose escalation will begin until an RP2D is determined. In Part 2, the clinical activity (disease control rate atWeek 16 based on RECIST 1.1) and safety of GSK2879552 will be evaluated at the RP2D in an expansion cohort of <30 patients with recurrent SCLC. Patients must have received <2 prior chemotherapy regimens, including >1 containing platinum, and have measurable disease. Results: Additional study objectives include: analysis of pharmacokinetics of GSK2879552 after single and repeat dosing, evaluation of the relationship between GSK2879552 exposure and safety/efficacy/pharmacodynamic parameters, duration of response, progression-free survival, and objective response rate. Conclusions: Recruitment is ongoing across six centers (USA, France and Spain); 47 patients will be enrolled in Part 1 and 30 in Part 2.

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Moreno, V., Bauer, T. M., Infante, J., Govindan, R., Besse, B., Bertino, E., … Dhar, A. (2016). A phase I, open-label, study of GSK2879552, a lysine-specific demethylase 1 (LSD1) inhibitor, in patients with relapsed/refractory small cell lung carcinoma (SCLC). Annals of Oncology, 27, vi121. https://doi.org/10.1093/annonc/mdw368.24

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