A Phase I/II Study of Intravenous LBH589, a Novel Histone Deacetylase (HDAC) Inhibitor, in Patients (pts) with Advanced Hematologic Malignancies.

LBH589 is a novel HDAC inhibitor which activates p21 and inhibits proliferation and induces apoptosis in tumor cell lines at nanomolar concentrations. In this study, LBH589 was administered IV as a 30-minute infusion on days 1–7 of a 21 day cycle. Fourteen pts. (median 61 years [range 42–87], performance status 0 (2 pts) or 1 (12 pts), de novo AML (2 pts), relapsed /refractory AML (10 pts), refractory ALL (1 pt), MDS (RAEB) (1 pt) have been treated at dose levels (mg/m²): 4.8 (3 pts), 7.2 (3 pts), 9.0 (1 pt), 11.5 (2 pts), 14.0 (5 pts). Four DLT’s (G3 QTcF prolongation) have been observed − 3 at 14.0 mg/m² and one at 11.5 mg/m² (a total of 357 ECG’s were performed during the study). One patient treated at 14.0 mg/m² died of pulmonary hemmorhage resulting from sepsis while on study. Treatment with LBH589 as well as the patient’s underlying disease (MDS) were considered a contributing factors to the sepsis. A white cell differentiation syndrome (which was sucessfully treated with high-dose steroids) was observed in one patient with refractory AML treated at 14.0 mg/m². Other LBH589-related toxicities included: Grade 1 ST-T wave abnormality, palpitations, hypokalemia; Grade 2 diarrhea, nausea, vomiting, loss of appetite, headache, atrial fibrillation, and QT prolongation. In 9 of 12 patients (2 patients were aleukemic), treatment with LBH589 resulted in reductions in peripheral blasts, WBC and platelets during treatment. Counts rebounded following the 7-day treatment period (generally by day 15). Bone marrow blast counts generally continued to increase during treatment. The levels of histone acetylation in bone marrow and peripheral blood cells were measured using quantitative flow cytometry and antibodies against histones H2B and H3. The median acetylation of histones H2B and H3 in CD34+ cells increased on therapy from 4463 to 17185 and from 11540 to 66224, respectively. Despite this increase in histone acetylation a significant change in apoptosis (measured by annexin V or mitochondrial potential) or proliferation (measured by BrdU incorporation) in CD34+ cells was not demonstrated. However, peripheral blood lymphocytes showed significant increase in apoptosis on day 7 as compared with the levels of apoptosis before therapy. PK samples were collected on days 1 and 7 of cycle 1 and analyzed using a noncompartmental analysis. Plasma LBH589 concentrations were determined using HPLC/MS/MS assay. AUC increased proportionally with dose and mean AUCs (0–24h) were 139.47, 131.46, 189.12, and 344.28 ng.h/mL, respectively, for 4.8, 7.2, 9.0, and 14.0 mg/M² dose levels on Day 1. Terminal half-life was approximately 11 hrs. LBH589 given IV appears well tolerated at doses below 11.5 mg/m² with consistent transient antileukemic and PD effects.