Journal Article

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

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

2017

Overview

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/m 2 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/308/2779/109/1941 / 692/699/67/1990/1673 / 692/699/67/1990/283/1897 / 692/700/565/1436/1437 / Acute myeloid leukemia / Administration, Oral / Adult / Adults / Aged / Aged, 80 and over / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Azacitidine / Azacitidine - administration & dosage / Bone marrow / Bone Marrow - pathology / Cancer Research / Care and treatment / Chronic myelomonocytic leukemia / Critical Care Medicine / Diagnosis / Dosage and administration / Female / Hematology / Humans / Hydroxamic Acids - administration & dosage / Indoles - administration & dosage / Intensive / Internal Medicine / Kaplan-Meier Estimate / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - mortality / Leukemia, Myeloid, Acute - pathology / Leukemia, Myelomonocytic, Chronic - drug therapy / Leukemia, Myelomonocytic, Chronic - mortality / Leukemia, Myelomonocytic, Chronic - pathology / Male / Maximum Tolerated Dose / Medicine / Medicine & Public Health / Middle Aged / Myelodysplastic syndrome / Myelodysplastic syndromes / Myelodysplastic Syndromes - drug therapy / Myelodysplastic Syndromes - mortality / Myelodysplastic Syndromes - pathology / Myeloid leukemia / Myelomonocytic leukemia / Oncology / Optimization / Original / original-article / Patients / Quality / Risk / Slopes / Stem cell transplantation / Survival / Treatment Outcome