A Phase I Study of GSK2816126, an Enhancer of Zeste Homolog 2(EZH2) Inhibitor, in Patients (pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Other Non-Hodgkin Lymphomas (NHL), Transformed Follicular Lymphoma (tFL), Solid Tumors and Multiple Myeloma (MM)
Authors: Yap Timothy A. , Winter Jane N. , Leonard John P. , Ribrag Vincent , Constantinidou Anastasia , Giulino-Roth Lisa , Michot Jean-Marie , Khan Tariq A , Horner Thierry , Carver Jennifer , Pene Dumetrescu Teodora , He Zangdong , McCabe Michael T. , Creasy Caretha L. , Dhar Arindam , Carpenter Christopher , Johnson Peter M 
Published: October 2019

Abstract
Background: EZH2 is the methyltransferase component of the polycomb repressive complex 2 (PRC2) that represses transcription of target genes via trimethylation of histone H3 at lysine 27 (H3K27me3), resulting in proliferative and migratory activity. EZH2 deregulation (via mutation or overexpression) in many cancers is associated with a more aggressive cancer phenotype and poor prognosis. GSK2816126, a highly selective and potent inhibitor of both wild type (wt) and mutant (mut) EZH2, decreases H3K27 tri-methylation, releases transcriptional repression of PRC2 target genes and induces anti-proliferative activity in several EZH2 wt/mut cancer cell lines.
Methods: Part I of this 2-part study is a combined accelerated plus classic 3+3 with adaptive Bayesian design dose escalation of GSK2816126 in pts (≥18 years) with relapsed/refractory DLBCL, tFL, other NHL, MM and solid tumors. Primary objectives are to determine safety, tolerability and the recommended expansion dose. Secondary objectives include pharmacokinetic (PK) and pharmacodynamic (PD) analysis and preliminary evaluation of activity. Patients received two intravenous (IV) doses weekly for 3 weeks with one week off (3W-on/1W-off) in a 28 day cycle. Dose limiting toxicity (DLT) observation period for dose escalation was first 28 days.
Results: As of 13 June 2016 data cut, a total of 30 pts have been treated with 50mg (n=2), 100mg (n=1), 200mg (n=1), 400mg (n=1), 800mg (n=3), 1200mg (n=4), 1800mg (n=10), 2400mg (n=5) and 3000mg (n=3) of GSK2816126 given IV twice weekly (3W-on/1W-off). Tumor types included 10 DLBCL, 2 tFL, 2 other NHL (FL and MZL) and 16 solid tumors. Preliminary results demonstrate GSK2816126 is well tolerated with no DLTs observed. Dose expansion is ongoing at 3000 mg IV (3W-on/1W-off). The most common drug-related adverse events (AEs) reported at >20% incidence were fatigue (53%), nausea (30%), anemia (20%) and vomiting (20%). PK was linear from 50mg to 3000mg given twice weekly, with moderate to high inter-subject variability and no accumulation. At 3000mg, Cmax was 22 ±34.1 ng/mL; t ½ 33.3 ±11.5 hour; AUC (0-∞) 109.8 ±53.5 ng*h/mL. Of 22 evaluable pts, 1 durable confirmed partial response (PR) was observed in an advanced GCB+ DLBCL patient (1800mg GSK2816126). 7 patients had stable disease, including an advanced FL patient with 45% tumor regression and a cholangiocarcinoma patient lasting >6 cycles.
Conclusion: GSK2816126 is well tolerated with evidence of antitumor activity. Expansion of 3000 mg IV (3W-on/1W-off) is ongoing to confirm safety and efficacy. Part 2 of the study will enroll pts with EZH2 wt/mut GCB+ DLBCL and tFL, relapsed/refractory myeloma and solid tumors including castration-resistant and small cell prostate cancers.
This study was funded by GSK.

Disclosures
Winter: Medivation: Other: Provision of investigational agent for clinical trial; GSK: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Ribrag:Gilead, Infifnity, Pharmamarr, BMS, Esai, Incyte, Nanostring: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Michot:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Horner:GlaxoSmithKline: Employment. Carver:GSK: Employment. Pene Dumetrescu:GSK: Employment. He:GSK: Employment. McCabe:GSK: Employment. Creasy:GlaxoSmithKline: Employment. Dhar:GlaxoSmithKline: Employment. Carpenter:GSK: Employment. Johnson:Celldex Therapeutics: Research Funding.