Phase I Study of Entinostat, Atezolizumab, Carboplatin, and Etoposide in Previously Untreated Extensive-Stage Small Cell Lung Cancer, ETCTN 10399

Abstract

Background CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors. Methods Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%. Results Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls. Conclusion Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).

Epigenetic Regulation in Schizophrenia: Focus on Methylation and Histone Modifications in Human Studies

“…Valproate administration (which acts as a nonspecific HDAC inhibitor) has been reported to improve the clinical efficacy of atypical antipsychotic drugs (such as clozapine, risperidone, and olanzapine) [ 113 , 114 , 115 , 116 ], confirming the potential of HDAC inhibitors as new targets for SZ treatment. In the last few years, HDAC inhibitors have been extensively tested for different types of cancer therapy [ 117 , 118 , 119 ] and as cognitive enhancers [ 120 ], which may potentially help neurodegenerative diseases such as Alzheimer’s disease [ 121 ]. The use of HDAC inhibitors seems to have limited side effects and act as a permissive chromatin, making it accessible to all genes implicated in learning and memory.…”