A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia

摘要: Purpose:  To determine the safety, dose-limiting toxicity and maximum tolerated dose (MTD) of novel hydroxamate histone deacetylase inhibitor belinostat (PXD101) in patients with advanced hematological neoplasms. Patients methods:  Sequential dose-escalating cohorts three to six malignancies received administered as a 30-min i.v. infusion on days 1–5 21-d cycle. Experience from parallel dose-finding study solid tumors influenced selection final dose. Results:  Sixteen at one levels: 600 mg/m2/d (three patients), 900 mg/m2/d patients) 1000 mg/m2/d (10 determined be MTD phase I tumor [Steele et al. (2008) Clin Cancer Res, 14, 804–10]. The most common treatment-related adverse events (all grades) were nausea (50%), vomiting (31%), fatigue (31%) flushing (31%). No grade 3 or 4 compared baseline occurred except case lymphopenia. There two related renal failure observed. Both multiple myeloma had similar characteristics, i.e. an acute episode decrease function (pre-existing nephropathy patient), metabolic profile burden consistent lysis syndrome. other noted. The only noticed more than patient neurological symptoms (one status epilepticus association uremia paresthesia), all single patients. cardiac noted. No complete partial remissions noted these heavily pre-treated (median four prior regimens) However, five patients, including diffuse large-cell lymphoma [including transformed chronic myelomcytic leukaemia (CLL)], CLL myeloma, achieved disease stabilization nine treatment cycles. Conclusions:  Intravenous 600, 900 is well by malignancies. was carried out tumors, which This can also recommended for II studies neoplasms.