Phase I study of panobinostat and 5-azacitidine in Japanese patients with myelodysplastic syndrome or chronic myelomonocytic leukemia
The current therapy for high-risk myelodysplastic syndrome (MDS) involves repeated cycles of the DNA demethylating agent 5-azacitidine (5-Aza), but combination treatments have been proposed to improve patient outcomes. We performed a phase Ib study to investigate the safety and tolerability of 5-Aza (75 mg/m2) combined with the histone deacetylase inhibitor panobinostat (PAN) in adult Japanese patients with MDS or chronic myelomonocytic leukemia (CMML). Eleven patients were enrolled; five received 20 mg PAN + 5-Aza and six received 30 mg PAN + 5-Aza. All patients in the 20 mg PAN cohort had MDS, while two in the 30 mg PAN cohort had MDS and three had CMML. All patients experienced ≥1 adverse event (AE) related to the study treatment, and five discontinued the study treatment because of AEs. One patient in each group exhibited dose-limiting toxicities: lung infection (PAN 20 mg + 5-Aza) and cellulitis (PAN 30 mg + 5-Aza). PAN exposure increased with ascending doses, and combination therapy did not affect PAN plasma trough concentrations. In summary, 20 or 30 mg PAN combined with 5-Aza was safe and tolerable in adult Japanese patients with CMML or MDS.
Study registration ClinicalTrials.gov Identifier: NCT01613976.
KeywordsAzacitidine AML CMML Myelodysplastic syndromes Panobinostat
This study was supported by an independent data monitoring committee comprising three physicians: Dr. Yasushi Miyazaki of Nagasaki University, Dr. Keiya Ozawa of Jichi Medical University (currently of the Institute of Medical Science, The University of Tokyo), and Dr. Tomoki Naoe of Nagoya Medical Center. A medical expert consultancy agreement was made with Dr. Masamitsu Yanada of Fujita Health University. The authors thank J. Ludovic Croxford, Ph.D., of Edanz Medical Writing, on behalf of Springer Healthcare Communications, for providing medical writing support. This assistance was funded by Novartis Pharmaceuticals Japan.
Conflict of interest
YK received research funding from Novartis during the conduct of the study. FS, MY, FM, and TT are employees of Novartis. HM reports grants from Novartis during the conduct of the study; as well as grants from Fuji Film RI Pharma, AstraZeneca, Yakult Honsha, Berhringer Ingelheim, Astellas, Merck Serono, Sanofi, MSD, Nihon Shinyaku, Teijin Pharma, and Dainippon Sumitomo; grants and personal fees from Taisho Toyama Pharmaceutical, Novartis, Eisai, Kyowa Hakko Kirin, Chugai, Bristol Myers Squibb, Taiho, Daiichi-Sankyo, Ono, Pfizer, Eli Lilly, Takeda Pharmaceutical, and Asahi Kasei Pharma, and personal fees from Bayer, Kowa, Nippon Chemiphar, and Mochida Pharmaceutical, outside the submitted work. MO reports grants from SymBio and Celltrion and personal fees from Meiji Seika Pharma, Mundipharma, Celltrion, AstraZeneca, Takeda, Jansen Pharma, and Celgene, outside the submitted work. The remaining authors declare that they have no conflicts of interest. This industry-led study was sponsored by Novartis, who also supplied the study drugs.
- 9.Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Ottmann OG, DeAngelo DJ, Garcia-Manero G, Lübbert M, Jillella A, Sekeres MA et al. Determination of a phase II dose of panobinostat in combination with 5-azacitidine in patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia. American Society of Hematology (ASH)—annual meeting 2011, Abs # 459. https://ash.confex.com/ash/2011/webprogram/Paper37915.html. Accessed 19 Jan 2016.
- 33.Tikhonova IA, Hoyle MW, Snowsill TM, Cooper C, Varley-Campbell JL, Rudin CE, et al. Azacitidine for treating acute myeloid leukaemia with more than 30% bone marrow blasts: an evidence review group perspective of a National Institute for Health and Care Excellence single technology appraisal. Pharmacoeconomics. 2017;35:363–73.CrossRefPubMedGoogle Scholar