BACKGROUND: Relapsed and/or refractory acute myeloid leukemia (AML) has a poor prognosis and requires investigation into novel targets and therapies. Bromodomains (BRDs) are small protein domains that recognize and bind to acetylated histone tails, modify chromatin structure, and lead to upregulation of target genes to drive oncogenesis. Conversely, the inhibition of BRD and extraterminal domain (BET) family proteins by the small molecule GSK525762 prevents macromolecular complex assembly and the subsequent transcriptional response. GSK525762 has broad activity against a spectrum of human hematological cancers, including in vitro and in vivo in xenograft models of AML cell lines. Study BET116183 was designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of GSK525762 in relapsed and refractory hematologic malignancies, including AML. Here we report the results from the AML dose escalation cohort.

METHODS: Eligible subjects were adults with relapsed or refractory AML. An accelerated dose titration design allowed one subject per dose level until the occurrence of a ≥Grade 2 drug-related toxicity or dose-limiting toxicity (DLT); thereafter, a standard 3+3 design was used until the maximum tolerated dose (MTD) was identified. A Neuenschwander continual reassessment method (N-CRM) model was used to provide guidance for the next dose level. All data, including safety, tolerability, PK, PD, and efficacy, were used to identify the recommended part 2 dose (RP2D).

RESULTS: 46 subjects with AML received at least one dose of study drug (data cut 02 June 2017). Of these, 41 (89%) had relapsed/refractory AML, 4 (9%) had secondary AML (sAML) after myelodysplastic syndrome (MDS), and 1 (2%) had de novo AML. The median age was 66.5 years (range 24 to 84). The median number of prior treatments was 2.5 (range 0 to > 4).

The dose of GSK525762 was escalated from 5 mg orally QD to 120 mg QD. The median time on study was 0.72 months (range 0.1 to 14.3 months). Two DLTs were observed. One subject, treated at 100 mg QD, experienced intermittent Grade 3 diarrhea that began two days after discontinuing GSK525762 for unrelated toxicity; the subject was not re-challenged. A second subject, treated at 120 mg QD, experienced Grade 3 ejection fraction decrease; this reversed on discontinuation of GSK525762 for 12 days, and the subject was not re-challenged. Across all dose levels, 44 subjects (96%) experienced an adverse event (AE); 32 subjects (70%) experienced at least one AE that was deemed to be related to treatment with GSK525762. The most common related AEs were dysgeusia (n = 17; 37%), diarrhea (n = 15; 33%), nausea (n = 13; 28%), and elevated bilirubin (n = 7; 15%). Common Grade 3/4 related events included diarrhea (n = 4; 9%), febrile neutropenia (n = 3; 7%), and thrombocytopenia, hyperglycemia, and fatigue/asthenia (n = 2 [4%] each). No Grade 5 related AEs were reported. Two subjects (4%) required dose reduction for toxicity, one each at the 100 mg and 120 mg dose levels. As of the data cut, five responses were observed: three partial responses (PRs) (two at 60 mg and one at 80 mg), one complete response with incomplete count recovery (CRi) at 100 mg, and one complete response with incomplete platelet recovery (CRp) at 120 mg. Most responses were delayed, requiring at least 10 weeks of therapy to manifest.

PK analyses were performed after single and repeated administration. PK was dose-proportional with large between patient variability. PD target engagement was assessed in bone marrow at 60 mg and above using a 7-gene expression panel and showed a trend towards dose-dependent changes in gene expression.

CONCLUSIONS: Phase I data of the first study evaluating the safety and efficacy of the BET inhibitor GSK525762 in subjects with AML indicate that adverse events were manageable and reversible. Preliminary evidence of efficacy, including complete responses with incomplete peripheral count recovery, was observed. The dose of 75 mg, with an option to increase the dose to 100 mg after 14 days based on tolerability, was chosen as the RP2D. Based on the results from Part 1, Part 2 of the BET116183 study will evaluate the efficacy of GSK525762 in subjects with relapsed or refractory myelodysplastic syndrome (MDS), or with hypoproliferative AML (blast percentage ≤ 30%) that has arisen from an antecedent MDS.

Mark Dawson and Eytan Stein are co-lead authors.


Stein: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Seattle Genetics: Research Funding; GSK: Other: Advisory Board, Research Funding; Novartis: Consultancy, Research Funding; Constellation Pharma: Research Funding; Pfizer: Consultancy, Other: Travel expenses. Karadimitris: GlaxoSmithKline: Research Funding. Kamdar: Seattle Genetics: Speakers Bureau. Dickinson: GlaxoSmithKline: Honoraria, Research Funding. Daver: Jazz: Consultancy; Pfizer Inc.: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Immunogen: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Daiichi-Sankyo: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Kiromic: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy. Horner: GlaxoSmithKline: Employment. Baron: GlaxoSmithKline: Employment. Brennan: GlaxoSmithKline: Employment. Ferron-Brady: GlaxoSmithKline: Employment, Equity Ownership. Wu: GSK: Employment, Equity Ownership. Karpinich: GlaxoSmithKline: Employment. Kremer: GlaxoSmithKline: Employment, Other: GSK Stock. Dhar: GSK: Employment.

Author notes


Asterisk with author names denotes non-ASH members.