PMID- 37555284
OWN - NLM
STAT- MEDLINE
DCOM- 20231108
LR  - 20240104
IS  - 1549-490X (Electronic)
IS  - 1083-7159 (Print)
IS  - 1083-7159 (Linking)
VI  - 28
IP  - 11
DP  - 2023 Nov 2
TI  - Phase I Study of Entinostat, Atezolizumab, Carboplatin, and Etoposide in 
      Previously Untreated Extensive-Stage Small Cell Lung Cancer, ETCTN 10399.
PG  - 1007-e1107
LID - 10.1093/oncolo/oyad221 [doi]
AB  - 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-naive 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).
CI  - (c) The Author(s) 2023. Published by Oxford University Press.
FAU - Gentzler, Ryan D
AU  - Gentzler RD
AUID- ORCID: 0000-0002-8983-6677
AD  - Division of Hematology/Oncology, Department of Medicine, University of Virginia 
      Cancer Center, Charlottesville, VA, USA.
FAU - Villaruz, Liza C
AU  - Villaruz LC
AUID- ORCID: 0000-0001-7456-523X
AD  - Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh 
      Medical Center-Hillman Cancer Center, Pittsburgh, PA, USA.
FAU - Rhee, John C
AU  - Rhee JC
AD  - Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh 
      Medical Center-Hillman Cancer Center, Pittsburgh, PA, USA.
FAU - Horton, Bethany
AU  - Horton B
AUID- ORCID: 0000-0002-6866-4626
AD  - Department of Public Health Sciences, University of Virginia School of Medicine, 
      Charlottesville, VA, USA.
FAU - Mock, Joseph
AU  - Mock J
AD  - Division of Hematology/Oncology, Department of Medicine, University of Virginia 
      Cancer Center, Charlottesville, VA, USA.
FAU - Hanley, Michael
AU  - Hanley M
AUID- ORCID: 0000-0003-3400-1055
AD  - Department of Radiology and Medical Imaging, University of Virginia, 
      Charlottesville, VA, USA.
FAU - Kim, Kyeongmin
AU  - Kim K
AD  - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State 
      University, Columbus, OH, USA.
FAU - Rudek, Michelle A
AU  - Rudek MA
AUID- ORCID: 0000-0001-5739-6868
AD  - Department of Oncology and Medicine, The Sidney Kimmel Comprehensive Cancer 
      Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
FAU - Phelps, Mitch A
AU  - Phelps MA
AUID- ORCID: 0000-0002-1615-5280
AD  - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State 
      University, Columbus, OH, USA.
FAU - Carducci, Michael A
AU  - Carducci MA
AUID- ORCID: 0000-0002-7908-1215
AD  - Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University School of Medicine, Baltimore, MD, USA.
FAU - Piekarz, Richard
AU  - Piekarz R
AUID- ORCID: 0000-0002-3591-7893
AD  - Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
FAU - Park, Kwon-Sik
AU  - Park KS
AUID- ORCID: 0000-0003-3346-9086
AD  - Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, 
      University of Virginia Cancer Center, Charlottesville, VA, USA.
FAU - Bullock, Timothy N
AU  - Bullock TN
AUID- ORCID: 0000-0001-6141-3261
AD  - Department of Pathology, University of Virginia Cancer Center, Charlottesville, 
      VA, USA.
FAU - Rudin, Charles M
AU  - Rudin CM
AUID- ORCID: 0000-0001-5204-3465
AD  - Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering 
      Cancer Center, New York, NY, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT04631029
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - UM1 CA186690/CA/NCI NIH HHS/United States
GR  - UM1 CA186691/CA/NCI NIH HHS/United States
GR  - 2UM1CA186691-06 and 2UM1CA186690-06/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PL  - England
TA  - Oncologist
JT  - The oncologist
JID - 9607837
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - BG3F62OND5 (Carboplatin)
RN  - 52CMI0WC3Y (atezolizumab)
RN  - 1ZNY4FKK9H (entinostat)
SB  - IM
MH  - Humans
MH  - Male
MH  - Female
MH  - Etoposide
MH  - Carboplatin
MH  - *Small Cell Lung Carcinoma/drug therapy
MH  - *Lung Neoplasms/drug therapy
MH  - Bayes Theorem
MH  - *Neutropenia/chemically induced
MH  - *Thrombocytopenia/chemically induced
MH  - *Anemia/chemically induced
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
PMC - PMC10628589
OTO - NOTNLM
OT  - atezolizumab
OT  - carboplatin
OT  - entinostat
OT  - etoposide
OT  - immunotherapy
OT  - small cell lung cancer
COIS- 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.
EDAT- 2023/08/09 06:43
MHDA- 2023/11/08 06:42
PMCR- 2023/08/09
CRDT- 2023/08/09 04:33
PHST- 2023/05/27 00:00 [received]
PHST- 2023/07/10 00:00 [accepted]
PHST- 2023/11/08 06:42 [medline]
PHST- 2023/08/09 06:43 [pubmed]
PHST- 2023/08/09 04:33 [entrez]
PHST- 2023/08/09 00:00 [pmc-release]
AID - 7239521 [pii]
AID - oyad221 [pii]
AID - 10.1093/oncolo/oyad221 [doi]
PST - ppublish
SO  - Oncologist. 2023 Nov 2;28(11):1007-e1107. doi: 10.1093/oncolo/oyad221.