Determination of the Maximum Tolerated Dose of Panobinostat in Combination with a 5-Day Schedule of Azacitidine in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia: Planned Interim Analysis of a Phase Ib/II Study

The management options for patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy remain limited. The combination of hypomethylating agent and deacetylase inhibitor (DACi) has been shown to be synergistic, both in terms of leukaemia cell killing and gene reactivation in vitro.

To investigate the safety, tolerability and preliminary efficacy of combining the oral pan-DACi panobinostat (LBH589) with azacitidine in previously untreated MDS or AML, not fit for standard induction therapy.

Phase Ib/II multi-center open label dose-escalation and expansion study. Inclusion criteria: untreated IPSS intermediate-2 or high risk MDS, or AML (marrow blasts ≥20%), not eligible for standard induction therapy. Patients received azacitidine 75 mg/m² SC on days 1–5 of each 28-day cycle with 10, 20, 30 or 40mg panobinostat orally 3 days per week (M/W/F) for 7 doses per cycle commencing on day 5. The safety and tolerability of the combination was assessed.

This preliminary analysis includes 26 patients (M 17, F 9), median age 69 years (36–81). 18 AML patients had intermediate (11/18) or poor cytogenetic risk (7/18); 8 MDS patients with intermediate-2 (7/8) or high risk (1/8) IPSS. Patients were enrolled into panobinostat dose-escalation cohorts of 10mg (4 patients), 20mg (7), 30mg (6) or 40mg (6); and expansion study 30mg (3). All grade non-hematologic adverse events regardless of relatedness to study treatment (>10%) were: subcutaneous injection site redness or pain (57%), fatigue (48%), nausea (30%), anorexia (22%), diarrhoea (22%), dyspnoea (13%), fever (13%), hyperbilirubinemia (13%), hyperglycaemia (13%), hyponatremia (13%), leg oedema (13%) and light headedness (13%). There were no unexpected adverse events or drug reactions. The principal dose-limiting toxicity (DLT) was fatigue, as haematological toxicity was not considered dose-limiting. In the dose-escalation phase, the grade 3/4 DLTs were: panobinostat 10mg cohort (0/4 DLT), panobinostat 20mg cohort (1/7 DLT; grade 3 fatigue), panobinostat 30mg cohort (1/6 DLT; grade 3 fatigue), panobinostat 40mg (4/6 DLTs; all grade 3: fatigue (1), syncope (1), hyponatremia (1) and somnolence/reduced level of consciousness (1)). Therefore, in combination with the 5-day schedule of azacitidine, the maximum tolerated dose (MTD) of panobinostat was defined at 30mg; this dose level has been selected for expanded accrual. At present 10/26 patients (38%) remain on combination study therapy. The panobinostat dose has been reduced by one dose level in 5/26 patients (19%) due to fatigue; 3 patients from panobinostat 40mg cohort. In 16 patients taken off study, the most common cause was disease progression (9), infection (2), atrial fibrillation treated with panobinostat interacting medication (2), patient choice (2) and fatigue (1). The median number of treatment cycles initiated was 4 (1–16). Preliminary efficacy in 18 AML patients, 3 achieved PR, 7 SD, 7 PD and 1 death unrelated to disease or therapy. In 8 MDS patients, 2 achieved CR, 3 PR, 2 SD, and 1 not evaluable (withdrawal due to patient choice). After a median follow-up of 276 days, the median OS is 239 days (22–472).

In previously untreated MDS/AML, panobinostat and azacitidine is well tolerated and preliminary assessments demonstrate clinical activity. The MTD was determined to be 30mg of panobinostat in combination with a 5-day azacitidine schedule of 75mg/m² daily. Further evaluation of this combination with panobinostat 30mg dose is ongoing in the dose-expansion phase of the study.

Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees. Gervasio:Novartis: Employment. Winiger:Novartis AG: Employee, Employment, Equity Ownership, Honoraria. Hönemann:Celgene Pty Ltd: Employment. Wei:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Spencer:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.