Background: For patients (pts) with acute myeloid leukemia (AML) with poor prognostic indicators, such as unfavorable cytogenetics or secondary AML, overall and event-free survival (EFS) rates are much worse, highlighting the critical need for more effective therapeutic modalities. Increasing evidence implicates epigenetic processes in the development of AML. Panobinostat (PAN), a potent pan-deacetylase inhibitor, has been shown to augment the effects of standard chemotherapies (anthracyclines and Ara-C) in preclinical studies with AML cells. These preclinical results led to a phase 1b study of PAN in combination with idarubicin and Ara-C in pts with high-risk AML.

Methods: The trial included younger pts (≥ 18 y and ≤ 65 y) with newly diagnosed high-risk AML, defined as: treatment-related AML, AML following previously diagnosed myelodysplasia or medical history of relevant hematologic disorders, and presence of unfavorable cytogenetics. The primary objective was determination of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of PAN when given in combination with idarubicin and Ara-C. Secondary objectives included safety, efficacy, and pharmacokinetics (PK). Exploratory endpoints included assessment of the relationship between efficacy and PK parameters and 1-year EFS. The study examined escalating doses (15-25 mg) of PAN given 3 times per wk for 2 wk starting on day 8 of a 28-day cycle (ie, D8, D10, D12, D15, D17, D19) in combination with standard induction doses of idarubicin (12 mg/m2/d; D1-D3) and Ara-C (100 mg/m2/d; C1, D1-D7). After 2 cycles, pts achieving a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) moved to a consolidation phase with a combination of high-dose Ara-C and PAN at the dose received during induction. After determination of the RP2D, additional pts were enrolled in the expansion phase and treated at the RP2D dose.

Results: A total of 46 pts with a median age of 55.5 y (range, 19-65 y) were enrolled in the study (34 in the dose-escalation phase [15 mg, n = 11; 20 mg, n = 15; 25 mg, n = 8] and 12 in the dose-expansion phase). Seven dose-limiting toxicities were observed in the escalation phase: 4 of 12 pts in the 20-mg group (left ventricular systolic dysfunction [n = 2], hepatosplenic candidiasis [n = 1], increased QTCF [n = 1]) and 3 of 7 pts in the 25-mg group (febrile neutropenia [n = 2], grade 3 diarrhea [n = 1]). Based upon the Bayesian linear regression model, the upper limit (≤ 25% probability of excessive toxicity in > 33% of pts) was not reached for determination of MTD. The RP2D of PAN was 20 mg.

Among the 27 pts treated at the RP2D, common grade 3/4 adverse events (AEs) regardless of causality were mainly hematologic, including febrile neutropenia (59.3%), thrombocytopenia (48.1%), and anemia (40.7%). Although most pts experienced gastrointestinal AEs, they were largely grade ≤ 2 (all grades, 74.1%; grade 3/4, 11.1%). AEs led to discontinuation in 15% of pts treated at the RP2D. Four pts (3 of 46 during induction and 1 of 19 during consolidation) treated with RP2D died during treatment. Of the on-treatment deaths, 1 (grade 4 sepsis) was potentially related to study drug, whereas the remaining 3 (progressive AML, ischemic stroke, and cerebral hemorrhage) were determined to be unrelated. The geometric mean AUC0-24 of PAN after oral dosing increased with increasing PAN dose (42.5 hr•ng/mL [15 mg], 62.6 hr•ng/mL [20 mg], and 74.6 hr•ng/mL [25 mg]). However, AUC0-24 was higher in the expansion phase (92.7 hr•ng/mL) than at 25 mg in the escalation phase, with high variability (coefficient of variation, 32.3% [expansion]; 45.5% [25-mg escalation]). Among pts treated at the RP2D, 44.4% and 11.1% achieved CR and CRi, respectively (CR/CRi, 56%). In the subset of pts in the RP2D, no relationship was found between AUC0-24 and response rates. In the overall population, the 1-year EFS rate was 78.3%.

Conclusions: The data from this study showed high variability in PAN PK and largely overlapping exposure between dose levels. Overall, these data demonstrate a safety profile consistent with those of single-agent PAN and the combination of Ara-C and idarubicin.


DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Schlenk:Janssen: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sierra:Novartis: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Ocio:Novartis: Consultancy, Honoraria, Research Funding. Strickland:Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation. Valera:Novartis: Employment. Wegener:Novartis: Employment. De:Novartis: Employment. Mu:Novartis: Employment. Binlich:Novartis: Employment. Stuart:Novartis: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.