A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ≤30% blasts

G. Garcia-Manero, M. A. Sekeres, M. Egyed, M. Breccia, C. Graux, J. D. Cavenagh, H. Salman, A. Illes, P. Fenaux, D. J. Deangelo, R. Stauder, K. Yee, N. Zhu, J. H. Lee, D. Valcarcel, A. Macwhannell, Z. Borbenyi, L. Gazi, S. Acharyya, S. IdeM. Marker, O. G. Ottmann

Research output: Contribution to journalArticle

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Abstract

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is o2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n = 113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with o30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN +AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6-43.9%)) vs AZA (14.3% (5.4-28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50-80%); AZA, 70% (50-80%)) or time to progression (PAN+AZA, 70% (40-90%); AZA, 70% (40-80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-Treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

Original languageEnglish (US)
Pages (from-to)2799-2806
Number of pages8
JournalLeukemia
Volume31
Issue number12
DOIs
StatePublished - Jan 1 2017

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Azacitidine
Myelodysplastic Syndromes
Multicenter Studies
Maximum Tolerated Dose
panobinostat
Leukemia, Myelomonocytic, Chronic
Survival
Acute Myeloid Leukemia
Patient Care
Appointments and Schedules

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Garcia-Manero, G., Sekeres, M. A., Egyed, M., Breccia, M., Graux, C., Cavenagh, J. D., ... Ottmann, O. G. (2017). A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ≤30% blasts. Leukemia, 31(12), 2799-2806. https://doi.org/10.1038/leu.2017.159

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ≤30% blasts. / Garcia-Manero, G.; Sekeres, M. A.; Egyed, M.; Breccia, M.; Graux, C.; Cavenagh, J. D.; Salman, H.; Illes, A.; Fenaux, P.; Deangelo, D. J.; Stauder, R.; Yee, K.; Zhu, N.; Lee, J. H.; Valcarcel, D.; Macwhannell, A.; Borbenyi, Z.; Gazi, L.; Acharyya, S.; Ide, S.; Marker, M.; Ottmann, O. G.

In: Leukemia, Vol. 31, No. 12, 01.01.2017, p. 2799-2806.

Research output: Contribution to journalArticle

Garcia-Manero, G, Sekeres, MA, Egyed, M, Breccia, M, Graux, C, Cavenagh, JD, Salman, H, Illes, A, Fenaux, P, Deangelo, DJ, Stauder, R, Yee, K, Zhu, N, Lee, JH, Valcarcel, D, Macwhannell, A, Borbenyi, Z, Gazi, L, Acharyya, S, Ide, S, Marker, M & Ottmann, OG 2017, 'A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ≤30% blasts', Leukemia, vol. 31, no. 12, pp. 2799-2806. https://doi.org/10.1038/leu.2017.159
Garcia-Manero G, Sekeres MA, Egyed M, Breccia M, Graux C, Cavenagh JD et al. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ≤30% blasts. Leukemia. 2017 Jan 1;31(12):2799-2806. https://doi.org/10.1038/leu.2017.159
Garcia-Manero, G. ; Sekeres, M. A. ; Egyed, M. ; Breccia, M. ; Graux, C. ; Cavenagh, J. D. ; Salman, H. ; Illes, A. ; Fenaux, P. ; Deangelo, D. J. ; Stauder, R. ; Yee, K. ; Zhu, N. ; Lee, J. H. ; Valcarcel, D. ; Macwhannell, A. ; Borbenyi, Z. ; Gazi, L. ; Acharyya, S. ; Ide, S. ; Marker, M. ; Ottmann, O. G. / A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ≤30% blasts. In: Leukemia. 2017 ; Vol. 31, No. 12. pp. 2799-2806.
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abstract = "Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is o2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n = 113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with o30{\%} blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN +AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5{\%} (95{\%} CI, 14.6-43.9{\%})) vs AZA (14.3{\%} (5.4-28.5{\%})). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60{\%} (50-80{\%}); AZA, 70{\%} (50-80{\%})) or time to progression (PAN+AZA, 70{\%} (40-90{\%}); AZA, 70{\%} (40-80{\%})). More grade 3/4 adverse events (97.4 vs 81.0{\%}) and on-Treatment deaths (13.2 vs 4.8{\%}) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.",
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AU - Egyed, M.

AU - Breccia, M.

AU - Graux, C.

AU - Cavenagh, J. D.

AU - Salman, H.

AU - Illes, A.

AU - Fenaux, P.

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AU - Stauder, R.

AU - Yee, K.

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AU - Macwhannell, A.

AU - Borbenyi, Z.

AU - Gazi, L.

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AU - Ottmann, O. G.

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