Abstract CT038: A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin's lymphoma

Autor: Lillian L. Siu, Thierry Horner, Anthony W. Tolcher, Kimberley M. Heinhuis, Drew W. Rasco, Arindam Dhar, Brandon E. Kremer, Shelby A. Gorman, Olena Barbash, Sophie Postel-Vinay, Jacqueline L. Egger
Rok vydání: 2017
Předmět:
Zdroj: Cancer Research. 77:CT038-CT038
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2017-ct038
Popis: Background Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme responsible for symmetric arginine dimethylation of multiple proteins that impact cell proliferation. Its substrates include histones and proteins involved in signal transduction, gene transcription, DNA repair, and mRNA splicing. PRMT5 overexpression occurs in a number of different cancers, and higher expression is correlated with poor prognosis. Additional published data implicates PRMT5 in tumorigenesis, and as such it represents a novel target for therapeutic intervention in oncology. GSK3326595 is a potent, specific, and reversible inhibitor of PRMT5 that inhibits proliferation and induces cell death in a broad range of solid and hematologic tumor cell lines. It also exhibits potent antitumor activity in vivo in animal models. Methods Study 204653 is a Phase I, two-part, open-label, dose escalation/expansion study assessing the safety and tolerability of GSK3326595 in adult subjects with relapsed/refractory solid tumors and non-Hodgkin’s lymphoma. Dose escalation is being performed in subjects with solid tumors of any histology. An accelerated dose titration is employed with one subject per dose level until the occurrence of a ≥ Grade 2 non-disease related toxicity. Thereafter, subjects are enrolled in cohorts of approximately 3, and a modified toxicity probability interval (mTPI) method is used to guide dose escalation decisions. Dose escalation continues until the maximum tolerated dose (MTD) is identified. All data, including safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity, will be used to identify a recommended Phase 2 dose (RP2D). In Part 1, approximately 42 subjects are to be enrolled (30 subjects in dose escalation and an additional 12 subjects at or about the MTD to collect additional data, including PD and metabolites); no hypothesis will be tested, and all analysis will be descriptive and exploratory. In Part 2, the clinical activity of GSK3326595 will be evaluated in expansion cohorts of subjects with select tumor types. Based on preclinical data, enrollment is initially limited to subjects with triple-negative breast cancer (TNBC), metastatic bladder cancer (mBC), glioblastoma multiforme (GBM), and non-Hodgkin’s lymphoma (NHL); additional cohorts may be added based on emerging preclinical and clinical data. Two cohorts of NHL are scheduled, allocated by TP53 wild type versus mutant status. Up to 138 subjects may be enrolled in Part 2, and cohorts may be closed early for futility. As of 17 January 2017, recruitment is ongoing across four centers (USA, Canada, Netherlands, and France), and four subjects have been enrolled into the dose-escalation cohorts. ClinicalTrials.gov identifier: NCT02783300 Study is funded by GlaxoSmithKline Citation Format: Drew Rasco, Anthony Tolcher, Lillian L. Siu, Kimberley Heinhuis, Sophie Postel-Vinay, Olena Barbash, Jacqueline L. Egger, Shelby Gorman, Thierry Horner, Arindam Dhar, Brandon E. Kremer. A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT038. doi:10.1158/1538-7445.AM2017-CT038
Databáze: OpenAIRE
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