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Phase I study of the novel Enhancer of Zeste Homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors

Phase I study of the novel Enhancer of Zeste Homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors
Phase I study of the novel Enhancer of Zeste Homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors

BACKGROUND: 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.

CONCLUSION: 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.

1078-0432
Yap, Timothy A.
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Winter, Jane N.
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Giulino-Roth, Lisa
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Longley, Jemma
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Lopez, Juanita
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Michot, Jean-Marie
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Leonard, John P.
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Ribrag, Vincent
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McCabe, Michael T.
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Creasy, Caretha L.
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Stern, Melissa
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Pene Dumitrescu, Teodora
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Wang, Xiaowei
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Frey, Steve
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Carver, Jennifer
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Horner, Thierry
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Oh, Choon
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Khaled, Ahmed
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Dhar, Arindam
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Johnson, Peter W.M.
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Yap, Timothy A.
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Winter, Jane N.
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Giulino-Roth, Lisa
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Longley, Jemma
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Lopez, Juanita
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Michot, Jean-Marie
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Leonard, John P.
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Ribrag, Vincent
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McCabe, Michael T.
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Creasy, Caretha L.
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Stern, Melissa
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Pene Dumitrescu, Teodora
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Wang, Xiaowei
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Frey, Steve
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Carver, Jennifer
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Horner, Thierry
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Oh, Choon
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Khaled, Ahmed
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Dhar, Arindam
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Johnson, Peter W.M.
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Yap, Timothy A., Winter, Jane N., Giulino-Roth, Lisa, Longley, Jemma, Lopez, Juanita, Michot, Jean-Marie, Leonard, John P., Ribrag, Vincent, McCabe, Michael T., Creasy, Caretha L., Stern, Melissa, Pene Dumitrescu, Teodora, Wang, Xiaowei, Frey, Steve, Carver, Jennifer, Horner, Thierry, Oh, Choon, Khaled, Ahmed, Dhar, Arindam and Johnson, Peter W.M. (2019) Phase I study of the novel Enhancer of Zeste Homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors. Clinical Cancer Research. (doi:10.1158/1078-0432.CCR-18-4121).

Record type: Article

Abstract

BACKGROUND: 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.

CONCLUSION: 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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Accepted/In Press date: 27 August 2019
e-pub ahead of print date: 30 August 2019

Identifiers

Local EPrints ID: 436432
URI: http://eprints.soton.ac.uk/id/eprint/436432
ISSN: 1078-0432
PURE UUID: 678da8c1-f609-4d41-b727-675ec0518d36
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974

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Date deposited: 10 Dec 2019 17:30
Last modified: 10 Jan 2022 05:26

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Contributors

Author: Timothy A. Yap
Author: Jane N. Winter
Author: Lisa Giulino-Roth
Author: Jemma Longley
Author: Juanita Lopez
Author: Jean-Marie Michot
Author: John P. Leonard
Author: Vincent Ribrag
Author: Michael T. McCabe
Author: Caretha L. Creasy
Author: Melissa Stern
Author: Teodora Pene Dumitrescu
Author: Xiaowei Wang
Author: Steve Frey
Author: Jennifer Carver
Author: Thierry Horner
Author: Choon Oh
Author: Ahmed Khaled
Author: Arindam Dhar

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