PMID- 38036712 OWN - NLM STAT- MEDLINE DCOM- 20240103 LR - 20240106 IS - 1432-0584 (Electronic) IS - 0939-5555 (Linking) VI - 103 IP - 1 DP - 2024 Jan TI - A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents. PG - 105-116 LID - 10.1007/s00277-023-05552-4 [doi] AB - Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic >/=G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752. CI - (c) 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Bewersdorf, Jan Philipp AU - Bewersdorf JP AUID- ORCID: 0000-0003-3352-0902 AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. jan.bewersdorf@yale.edu. AD - Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. jan.bewersdorf@yale.edu. FAU - Shallis, Rory M AU - Shallis RM AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. FAU - Sharon, Elad AU - Sharon E AD - Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. FAU - Park, Silvia AU - Park S AD - Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Ramaswamy, Rahul AU - Ramaswamy R AD - Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Roe, Caroline E AU - Roe CE AD - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. AD - Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA. FAU - Irish, Jonathan M AU - Irish JM AD - Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. AD - Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA. FAU - Caldwell, Anne AU - Caldwell A AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. FAU - Wei, Wei AU - Wei W AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. FAU - Yacoub, Abdulraheem AU - Yacoub A AD - The Division of Hematologic Malignancies and Cellular Therapeutics (HMCT), The University of Kansas Cancer Center, Westwood, KS, USA. FAU - Madanat, Yazan F AU - Madanat YF AD - Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA. FAU - Zeidner, Joshua F AU - Zeidner JF AD - Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC, USA. FAU - Altman, Jessica K AU - Altman JK AD - Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA. FAU - Odenike, Olatoyosi AU - Odenike O AD - University of Chicago, Chicago, IL, USA. FAU - Yerrabothala, Swaroopa AU - Yerrabothala S AD - Hitchcock Cancer Center, Dartmouth University, Lebanon, NH, USA. FAU - Kovacsovics, Tibor AU - Kovacsovics T AD - University of Utah, Huntsman Cancer Center, Salt Lake City, UT, USA. FAU - Podoltsev, Nikolai A AU - Podoltsev NA AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. FAU - Halene, Stephanie AU - Halene S AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. FAU - Little, Richard F AU - Little RF AD - Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. FAU - Piekarz, Richard AU - Piekarz R AD - Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. FAU - Gore, Steven D AU - Gore SD AD - Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. FAU - Kim, Tae Kon AU - Kim TK AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. tae.k.kim@vumc.org. AD - Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. tae.k.kim@vumc.org. AD - Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. tae.k.kim@vumc.org. AD - Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA. tae.k.kim@vumc.org. FAU - Zeidan, Amer M AU - Zeidan AM AD - Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. amer.zeidan@yale.edu. AD - Hematology Section, Department of Internal Medicine, Yale School of Medicine, Yale University, 333 Cedar Street, PO Box 208028, New Haven, CT, 06520-8028, USA. amer.zeidan@yale.edu. LA - eng SI - ClinicalTrials.gov/NCT02936752 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20231201 PL - Germany TA - Ann Hematol JT - Annals of hematology JID - 9107334 RN - 0 (Histone Deacetylase Inhibitors) RN - 1ZNY4FKK9H (entinostat) RN - DPT0O3T46P (pembrolizumab) SB - IM MH - Humans MH - Histone Deacetylase Inhibitors/adverse effects MH - *Myelodysplastic Syndromes/drug therapy/etiology MH - *Leukemia, Myeloid, Acute/drug therapy/etiology MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects OTO - NOTNLM OT - AML OT - Entinostat OT - MDS OT - Myeloid-derived suppressor cells OT - Pembrolizumab EDAT- 2023/12/01 00:43 MHDA- 2024/01/03 09:44 CRDT- 2023/11/30 23:43 PHST- 2023/09/28 00:00 [received] PHST- 2023/11/13 00:00 [accepted] PHST- 2024/01/03 09:44 [medline] PHST- 2023/12/01 00:43 [pubmed] PHST- 2023/11/30 23:43 [entrez] AID - 10.1007/s00277-023-05552-4 [pii] AID - 10.1007/s00277-023-05552-4 [doi] PST - ppublish SO - Ann Hematol. 2024 Jan;103(1):105-116. doi: 10.1007/s00277-023-05552-4. Epub 2023 Dec 1.