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Clinical Trial
. 2019 Dec 15;25(24):7331-7339.
doi: 10.1158/1078-0432.CCR-18-4121. Epub 2019 Aug 30.

Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors

Timothy A Yap  1 , Jane N Winter  2 , Lisa Giulino-Roth  3 , Jemma Longley  4 , Juanita Lopez  5 , Jean-Marie Michot  6 , John P Leonard  3 , Vincent Ribrag  6 , Michael T McCabe  7 , Caretha L Creasy  7 , Melissa Stern  7 , Teodora Pene Dumitrescu  7 , Xiaowei Wang  7 , Steve Frey  7 , Jennifer Carver  7 , Thierry Horner  7 , Choon Oh  7 , Ahmed Khaled  7 , Arindam Dhar  7 , Peter W M Johnson  8
Affiliations
Clinical Trial

Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors

Timothy A Yap et al. Clin Cancer Res. .

Abstract

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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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

T. Yap is an employee/paid consultant for Aduro, Almac, AstraZeneca, Atrin, Bayer, Bristol-Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Jansen, Merck, Pfizer, Roche, Seattle Genetics, and Vertex Pharmaceuticals; reports commercial research funding from AstraZeneca, Bayer, Pfizer, Tesaro, Jounce, Eli Lilly, Seattle Genetics, Kyowa, Constellation, and Vertex Pharmaceuticals; and reports honoraria from AstraZeneca, Merck, Pfizer, and Tesaro. J.N. Winter is an employee/paid consultant for AstraZeneca, Merck, Bayer, Gilead, and Adicet Bio. L. Giulino-Roth is an employee/paid consultant for Janssen, Celgene, and ADC Therapeutics, and is an unpaid consultant/advisory board member for Merck. J. Lopez reports receiving commercial research grants from Basilea, Genmab, and Roche Genentech. J. Michot is an employee/paid consultant for Atheneum; holds ownership interest (including patents) in Celgene; and reports receiving other remuneration from Novartis. J.P. Leonard is an employee/paid consultant for Sutro, Bayer, Gilead, Celgene, Merck, Mophosys, Beigene, Nordic Nanovector, Roche/Genentech, ADC Therapeutics, Sandoz, Karyopharm, Miltenyi, Akcea Therapeutics, and Epizyme, and reports receiving commercial research grants from GlaxoSmithKline. V. Ribrag is an employee/paid consultant for Infinity Pharmaceuticals, Bristol-Myers Squibb, PharmaMar, Gilead Sciences, NanoString Technologies, Incyte, Bristol-Myers Squibb, MSD, Roche/Genentech, Epizyme, Immune Design, and Roche; receives commercial research grants from arGEN-X BVBA and his institution receives research grants from Epizyme; receives honoraria from Infinity Pharmaceuticals, Bristol-Myers Squibb, Eisai, PharmaMar, Gilead Sciences, AZD, Epizyme, Incyte, MSD, and SERVIER; reports receving other remuneration from SERVIER, Roche, Bristol-Myers Squibb, and AZD. M.T. McCabe is an employee/paid consultant for and holds ownership interest (including patents) in GlaxoSmithKline. C.L. Creasy is an employee/paid consultant for and holds ownership interest (including patents) in GlaxoSmithKline. M. Stern is an employee/paid consultant for GlaxoSmithKline. T. Pene Dumitrescu is an employee/paid consultant for GlaxoSmithKline. X. Wang is an employee/paid consultant for GlaxoSmithKline. S. Frey is an employee/paid consultant for and holds ownership interest (including patents) in GlaxoSmithKline. J. Carver is an employee/paid consultant for and holds ownership interest (including patents) in GlaxoSmithKline. T. Horner is an employee/paid consultant for and holds ownership interest (including patents) in GlaxoSmithKline. C. Oh is an employee/paid consultant for GlaxoSmithKline. A. Khaled is an employee/paid consultant for and holds ownership interest (including patents) in GlaxoSmithKline. A. Dhar is an employee/paid consultant for and holds ownership interest (including patents) in GlaxoSmithKline. P.W.M. Johnson is an employee/paid consultant for Takeda, Bristol-Myers Squibb, Novartis, Celgene, Kite Pharma, Genmab, Incyte, Morphosys, Kymera, Janssen, and Oncimmune, and reports receiving commercial research grants from Epizyme and Janssen. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
Study design. Patients could continue treatment in the study until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent. In part 1, the dose was escalated based on all available data.
Figure 2.
Figure 2.
Mean plasma concentration-time plots (linear and semilogarithmic) for cycle 1, day 1 and day 15. Mean plasma GSK2816126 concentration–time plots are shown for cycle 1, day 1 visit (A and B) and cycle 1, day 15 visit (C and D) by nominal time on a linear scale (A and C) and a semilogarithmic scale (B and D). The dotted line in panels B and D represents the lower limit of quantitation (5 ng/mL). The protein-binding adjusted IC50 for H3K27me3 (475 ng/mL) is indicated by an arrow on B and D.
Figure 3.
Figure 3.
Computed tomography scans of a patient with a partial response. The encircled area represents the soft tissue component associated with a rib lesion.
See this image and copyright information in PMC

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