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 Ide, M Marker, O G Ottmann, 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 Ide, M Marker, O G Ottmann

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 <2 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 <30% 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.

Trial registration: ClinicalTrials.gov NCT00946647.

Conflict of interest statement

GG-M, ME, JDC, HS, PF, NZ, J-HL, AM and ZB declare no conflict of interest; MAS has served on the board of directors/advisory committees for Celgene; MB has received honoraria from Novartis, BMS, Pfizer and Ariad; CG has received honoraria from and has served on the board of directors/advisory committees for Celgene, Novartis and Amgen; AI has served on the board of directors/advisory committees for Roche, Takeda and Janssen; DJD has held consulting and advisory roles with Ariad, BMS, Novartis, Pfizer, Incyte and Amgen; RS has received research funding and honoraria from Novartis, Celgene and Teva, has received honoraria from Hospira, and has served on the board of directors/advisory committees for Celgene; KY has served on the board of directors/advisory committees for Novartis and Celgene and has received research funding from Novartis, Celgene and Astex, and honoraria from Novartis; DV has received honoraria from and has served on the speaker's bureaus and board of directors/advisory committees for Celgene, Novartis, Amgen, Takeda and Pfizer, has held a consulting role with Celgene, has received honoraria from and served on the board of directors/advisory committees for Boehringer Ingelheim, and has received honoraria from and served on the speaker's bureau for Astellas; LG and SA are employees of Novartis; SI and MM are employees of and have equity ownership of Novartis; OGO has held a consulting role, has received research funding and honoraria from, and has served on the board of directors/advisory committees for Novartis.

Figures

Figure 1
Figure 1
Study design. In phase 1b, patients received escalating doses of PAN in combination with AZA. In phase 2b, patients were randomized to receive treatment with either the RP2D of PAN+AZA or single-agent AZA. AML, acute myeloid leukemia; AZA, azacitidine; CMML, chronic myelomonocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; IPSS Int-2, International Prognostic Scoring System intermediate 2; MDS, myelodysplastic syndrome; MTD, maximum tolerated dose; PAN, panobinostat; RP2D, recommended phase 2 dose.
Figure 2
Figure 2
Overall survival analysis. Kaplan−Meier curves are shown for patients randomized to receive PAN+AZA vs AZA alone. Symbols represent censoring times for patients in the PAN+AZA (squares) or AZA (triangles) arms, respectively. AZA, azacitidine; OS, overall survival; PAN, panobinostat.
Figure 3
Figure 3
Next-generation sequencing analysis. Patients with next-generation sequencing (NGS) data are from phase 2b. A gene is considered to be mutant (MT) if one or more alterations, regardless of functional significance, are detected. AML, acute myeloid leukemia; AZA, azacitidine; BM-CR, bone marrow complete response; CMML, chronic myelomonocytic leukemia; CR, complete response; CRi, morphologic CR with incomplete blood count; MDS, myelodysplastic syndrome; PAN, panobinostat; WT, wild type.

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