TY - JOUR
T1 - Phase I study of the novel enhancer of zeste homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors
AU - Yap, Timothy A.
AU - Winter, Jane N.
AU - Giulino-Roth, Lisa
AU - Longley, Jemma
AU - Lopez, Juanita
AU - Michot, Jean Marie
AU - Leonard, John P.
AU - Ribrag, Vincent
AU - McCabe, Michael T.
AU - Creasy, Caretha L.
AU - Stern, Melissa
AU - Dumitrescu, Teodora Pene
AU - Wang, Xiaowei
AU - Frey, Steve
AU - Carver, Jennifer
AU - Horner, Thierry
AU - Oh, Choon
AU - Khaled, Ahmed
AU - Dhar, Arindam
AU - Johnson, Peter W.M.
N1 - Funding Information:
All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Editorial support (assembling tables and figures, collating author comments, copyediting, fact checking, and referencing) and graphic services were provided by AOI Communications, L.P., and were funded by GlaxoSmithKline. The authors would like to thank Fabio Rigat for his contribution to the analysis of the PBMC H3K27me3 data and Uma Kamasani for her contribution to the analysis and reporting and with generating figures. Funding for this study (ClinicalTrials.gov Identifier: NCT02082977, www.clinicaltrials.gov) was provided by GlaxoSmithKline.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - Purpose: Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers. Patients and Methods: This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen. Results: Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response. Conclusions: The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
AB - Purpose: Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers. Patients and Methods: This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen. Results: Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response. Conclusions: The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
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U2 - 10.1158/1078-0432.CCR-18-4121
DO - 10.1158/1078-0432.CCR-18-4121
M3 - Article
C2 - 31471312
AN - SCOPUS:85076505599
SN - 1078-0432
VL - 25
SP - 7331
EP - 7339
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -