Abstract P3-11-06: A phase 1 study of KHK2375 (entinostat) as monotherapy and in combination with exemestane in Japanese patients with hormone receptor-positive, HER2-negative, advanced or recurrent breast cancer
Authors: Shimomura A , Masuda N , Tamura K , Yasojima H , Sawaki M , Nishimura Y , Saji S , Iwata H 
Published: February 2018

Abstract
Background: Patients (pts) with hormone receptor-positive (HR+) and non-life threatening advanced or metastatic breast cancer (BC) are usually treated with sequential endocrine therapies. Endocrine therapies are continued until tumor cells acquire resistance to them, following which pts are switched to cytotoxic chemotherapy. Entinostat (ENT) is an oral inhibitor of class I histone deacetylases (HDACs) and is expected to be used for endocrine therapy-resistant pts. The efficacy of ENT in combination with an aromatase inhibitor (AI) for HR+ BC was demonstrated in a previous randomized phase 2 study. Because of the lack of data on safety and pharmacokinetics (PK) in Japanese HR+ BC pts, we performed this dose escalation phase 1 study to investigate the safety of ENT monotherapy and combination therapy with exemestane (EXE) in postmenopausal women with advanced or recurrent HR+ BC. Secondary objectives were to assess PK and efficacy.
Methods: This study was based on a 3+3 dose escalation design. Postmenopausal women with advanced or recurrent HR+ HER2- BC previously treated with nonsteroidal AIs and with ECOG PS 0-1 were enrolled. The dose limiting toxicities (DLT) of ENT monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) in Cohort 1-3 and those of ENT (5 mg/qw or 3 mg/qw) in combination with EXE 25 mg/qd in Cohort 4-5 were assessed for 7 and 28 days, respectively. Pts continued ENT (3 mg or 5 mg) in combination with EXE even after the DLT observation period until disease progression or discontinuation for other reasons. Adverse events (AEs) were graded per NCI-CTCAE version 4.03. Tumor response was evaluated by RECIST version 1.1 every 8 weeks. ENT concentration was measured intensively. Samples of peripheral blood mononuclear cells (PBMC) were collected to measure protein lysine hyperacetylation and for immune subset analysis. Optional tumor biopsies for biomarker assessment were collected before and during treatment.
Results: Twelve pts were enrolled and three each were assigned to Cohort 1-4 between Nov 2015 and Sept 2016. Neither DLT nor grade 3-5 AE occurred. As no DLT occurred in Cohort 4, Cohort 5 was omitted as originally planned. The drug-related AEs observed in ≥2 pts during the DLT observation period were grade 1-2 hypophosphatemia (1 pt each in Cohort 2, 3, and 4), grade 1 nausea (1 pt in Cohort 3 and 2 pts in Cohort 4), and grade 1-2 platelet count decreased (2 pts in Cohort 4). AUC0-168 increased in a dose proportional manner. As of May 2017, 4 pts continue to receive study treatment, including one treated for more than 18 months. Biomarker data including protein lysine hyperacetylation and immune subset in PBMC and results of paired biopsy samples will be reported.
Conclusions: This study showed the tolerability of the combination therapy of ENT 5 mg with EXE 25 mg in Japanese pts. There were no new safety concerns as compared to those reported previously. Following this result, a randomized phase 2 study for Japanese pts is planned.
Clinical trial information : NCT02623751.
Citation Format: Shimomura A, Masuda N, Tamura K, Yasojima H, Sawaki M, Nishimura Y, Saji S, Iwata H. A phase 1 study of KHK2375 (entinostat) as monotherapy and in combination with exemestane in Japanese patients with hormone receptor-positive, HER2-negative, advanced or recurrent breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-06.