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Clinical Trial
. 2023 Nov 2;28(11):1007-e1107.
doi: 10.1093/oncolo/oyad221.

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

Ryan D Gentzler  1 , Liza C Villaruz  2 , John C Rhee  2 , Bethany Horton  3 , Joseph Mock  1 , Michael Hanley  4 , Kyeongmin Kim  5 , Michelle A Rudek  6 , Mitch A Phelps  5 , Michael A Carducci  7 , Richard Piekarz  8 , Kwon-Sik Park  9 , Timothy N Bullock  10 , Charles M Rudin  11
Affiliations
Clinical Trial

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

Ryan D Gentzler et al. Oncologist. .

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).

Keywords: atezolizumab; carboplatin; entinostat; etoposide; immunotherapy; small cell lung cancer.

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Conflict of interest statement

Ryan D. Gentzler reported consulting/advisory relationships with AstraZeneca, Takeda, Gilead, Janssen, Mirati, Daiichi Sankyo, Sanofi, Oncocyte, Jazz Pharmaceuticals, and BluePrint Medicines; research funding from Pfizer, Chugai, Amgen, Mirati, Daiichi Sankyo, BMS, AstraZeneca, Jounce Therapeutics, Helsinn, Takeda, and Merck; and honoraria from Clinical Care Options, OncLive, Targeted Oncology, SITC. Liza C Villaruz reported consulting/advisory relationships with Janssen, Interven Biosciences, Sanofi, Takeda, Jazz, and BMS, and research funding from AstraZeneca, Genentech, Jazz, Regeneron, Merck, GSK, BMS, Black Diamond Therapeutics, Janssen, BioAtla, and Amgen. Michelle A. Rudek reported research funding from Cullinan Apollo and Taiho Pharmaceutical. Timothy Bullock reported research funding from Tesaro/Glaxo, Celldex, and Merck, and honoraria from SVB Leerink. Charles M. Rudin reported consulting/advisory relationships with AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros, and scientific advisory board member for Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. The other authors indicated no financial relationships.

References

    1. Jia D, Augert A, Kim D-W, et al. . Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition. Cancer ­Discov. 2018;8(11):1422-1437. 10.1158/2159-8290.CD-18-0385 - DOI - PMC - PubMed
    1. Terranova-Barberio M, Thomas S, Ali N, et al. . HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget. 2017;8(69):114156-114172. 10.18632/oncotarget.23169 - DOI - PMC - PubMed
    1. Zheng H, Zhao W, Yan C, et al. . HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2016;22(16):4119-4132. 10.1158/1078-0432.CCR-15-2584 - DOI - PMC - PubMed
    1. Hellmann M, Janne P, Opyrchal M, et al. . OA05.01 efficacy/safety of entinostat (ENT) and pembrolizumab (PEMBRO) in NSCLC patients previously treated with anti-PD-(L)1 therapy. J Thoracic Oncol. 2018b;13(10):S330. 10.1016/j.jtho.2018.08.257 - DOI
    1. Liu S, Yuan Y.. Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc C. 2015;64(3):507-523. 10.1111/rssc.12089 - DOI

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