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Clinical Trial
. 2025 Mar;104(3):1577-1585.
doi: 10.1007/s00277-024-06081-4. Epub 2025 Mar 28.

A phase 1 study of durvalumab as monotherapy or combined with tremelimumab with or without azacitidine in patients with myelodysplastic syndrome

Guillermo Garcia-Manero  1 , Manila Gaddh  2 , Uwe Platzbecker  3 , R Coleman Lindsley  4 , Sarah M Larson  5 , Timothy Chevassut  6 , Pierre Fenaux  7 , Rami Komrokji  8 , Roger Lyons  9 , Aref Al-Kali  10 , Yu Jiang  11 , John Bothos  12 , Danielle M Townsley  12 , Amer M Zeidan  13
Affiliations
Clinical Trial

A phase 1 study of durvalumab as monotherapy or combined with tremelimumab with or without azacitidine in patients with myelodysplastic syndrome

Guillermo Garcia-Manero et al. Ann Hematol. 2025 Mar.

Abstract

Upregulation of programmed death ligand-1 (PD-L1) has been observed in patients with MDS, and its expression on myeloblasts is associated with progression to AML. This open-label, phase 1 study evaluated the safety and tolerability of the PD-L1 antibody durvalumab as monotherapy (part 1) and in combination with tremelimumab, with or without azacitidine (part 2), in patients with MDS who progressed following hypomethylating agent treatment. Sixty-seven adults with MDS were enrolled (part 1, 40 with low/intermediate-1 or intermediate-2/high IPSS risk status; part 2, 27 with intermediate-2/high IPSS risk status). Primary safety endpoints included dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). Secondary endpoints included evaluation of clinical outcomes, survival, and pharmacokinetics. Dose-limiting toxicities were experienced by no patients in part 1 and 3 patients (11%) in part 2. The most common treatment-emergent adverse events were diarrhea and fatigue (40% each) in part 1 and fatigue (44%) and anemia (37%) in part 2. In parts 1 and 2, 15% of patients experienced marrow complete response as their best overall response, according to IWG criteria. Hematologic improvement was observed in 35% and 30% of patients respectively in part 1 and part 2. The study was terminated early due to limited efficacy.

Keywords: Acute myeloid leukemia; CTLA-4; Durvalumab; First-in-human; MDS; PD-L1.

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Conflict of interest statement

Declarations. Ethics approval and patient consent: The study protocol and patient informed consent documents were approved by an institutional review board or independent ethics committee at each study site prior to initiation of the study. All patients provided written informed consent prior to participation. Clinical trial registration: This study is registered with ClinicalTrials.gov, NCT02117219. Competing interests: Guillermo Garcia-Manero: Consulting for Genentech and Bristol-Meyers Squibb. Grants to institution from Amphivena, Novartis, AbbVie, Onconova, H3 Biomedicine, Merck, Curis, Janssen, Forty Seven, Aprea, Genentech, and Bristol-Meyers Squibb. Grants and other from Helsinn and Astex. Manila Gaddh: Advisory board for Pfizer, Agios, Hema Biologics, and Pharmacyclics LLC.Uwe Platzbecker: Grant support paid to GWT-TUD from Amgen; lecture fees and grant support, paid to the University of Leipzig; fees for serving on a steering committee, consulting fees, and travel support from Celgene; grant support paid to GWT-TUD from Janssen Biotech; grant support paid to University of Dresden from Merck and Novartis; and lecture fees from Novartis. R. Coleman Lindsley: Consulting for Bluebird Bio, Takeda Pharmaceuticals, and Jazz Pharmaceuticals. Research support from MedImmune and Jazz Pharmaceuticals. Sarah M. Larson: Research funding: Bioline, BMS, Janssen, Takeda, Celgene. Honoraria: Takeda. Consulting: BMS. Timothy Chevassut: Consultancy/honoraria for Celgene/BMS, JAZZ, Abbvie, and AstraZeneca/Medimmune. Pierre Fenaux: Honoraria and research grants (as GFM chairperson) from BMS, Janssen, Novartis, Abbvie, and Astex. Rami Komrokji: Speaker bureau for Celgene/BMS, JAZZ, Agios, and AbbVie. Consultancy/honoraria for Celgene/BMS, JAZZ, AbbVie, Agios, Acceleron, and Geron. Roger Lyons: Research and Leadership for McKesson Corp; Research support for Abbvie, Alexion, Amgen, Astra Zeneca, Bristol-Myers Squibb, Celgene, Epizyme, Gilead, Incyte, Jannsen, Karyopharm, Medimmune, Merck, Millenium, Seattle Genetics, Sunesis, Takeda, and TG Therapeutics. Aref Al-Kali: Research funding to institution from Celgene/BMS and Medimmune/AstraZeneca. John Bothos: Employee of AstraZeneca and may own stock or stock options. Danielle Townsley: Employee of AstraZeneca and may own stock or stock options. Yu Jiang: Employee of AstraZeneca and may own stock or stock options. Amer Zeidan: Amer Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA). A.M.Z. received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Trovagene, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, and Tyme. A.M.Z served on steering and independent data review committees for clinical trials for Novartis, Abbvie, and Janssen. A.M.Z received travel support for meetings from Pfizer, Novartis, and Trovagene.

Figures

Fig. 1
Fig. 1
Survival, as-treated population. A Progression-free survival, part 1. B Overall survival, part (1) C. Progression-free survival, part (2) D Overall survival, part 2. A azacitidine, D durvalumab, CI confidence interval, NE not estimable, NR median estimate could not be calculated, PFS progression-free survival, OS overall survival, Q4W every 4 weeks, T tremelimumab
See this image and copyright information in PMC

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