A Phase I/II Open-Label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Subjects with Relapsed, Refractory Hematologic Malignancies

Background: Bromodomains (BRDs) are domains found in a variety of proteins that recognize and bind to acetylated lysine residues in histone and other target proteins. The BRD and extra-terminal (BET) family of BRD-containing proteins bind to acetylated histone tails, alters chromatin structure and facilitates transcriptional complex localization to specific genes, thereby regulating gene transcription. The investigational agent GSK525762 is a potent small molecule inhibitor of the BET family of proteins that prevents assembly of macromolecular complexes and transcriptional response. GSK525762 inhibits growth in a broad spectrum of human hematological cancer cell lines, including cell lines derived from human patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), and multiple myeloma (MM). GSK525762 is orally bio-available and can cause tumor reduction and improved animal survival in in vivo xenograft models of hematologic malignancies. Methods: This is a Phase I/II, open-label, 2-part study. Part 1 is a dose-escalation phase to determine the safety, tolerability, and recommended Phase 2 dose (RP2D) of GSK525762 in adult subjects with relapsed/refractory AML, NHL, and MM. Dose escalation is performed independently for each of these three cohorts. An accelerated dose titration was employed with one subject per dose level until the occurrence of a ≥Grade 2 drug-related toxicity or dose-limiting toxicity; thereafter, subjects have been enrolled in a standard 3+3 design. A Neuenschwander continual reassessment method (N-CRM) model is used at each dose escalation decision to provide guidance for the next dose escalation level. Starting dose is 5 mg GSK525762 orally once daily and dose escalation continues until the MTD is identified. All data, including safety, tolerability, pharmacokinetics (PK), and efficacy, are used to identify the RP2D. In Part 1, approximately 60-70 subjects will be enrolled (approximately 20 in each of three disease-specific cohorts); no hypothesis is being tested, and all analysis will be descriptive and exploratory. In Part 2, the clinical activity of GSK525762 (overall response rate) will be evaluated in expansion cohorts of subjects with AML, NHL, and MM. Up to 32 subjects may be enrolled into the AML and NHL cohorts, and up to 37 subjects may be enrolled in the MM cohort. Cohorts may be closed early if they do not exceed futility assessment. In addition, an exploratory cohort of subjects with double-hit lymphoma (DHL) and triple-hit lymphoma (THL) will be enrolled to evaluate clinical activity in this patient population. Additional study objectives include analysis of PK after single and repeat dosing, evaluation of pharmacodynamics (PD) and the relationship between GSK525762 exposure and safety/efficacy/PD parameters. Recruitment is ongoing across five centers (USA, UK, and Australia). Currently, 40 subjects have been enrolled (29 AML, 8 NHL, and 3 with MM).

Study funded by GSK.