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

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Abstract Purpose: 

To determine the safety, dose-limiting toxicity and maximum tolerated dose (MTD) of the novel hydroxamate histone deacetylase inhibitor belinostat (PXD101) in patients with advanced hematological neoplasms. Patients and methods: 

Sequential dose-escalating cohorts of three to six patients with hematological malignancies received belinostat administered as a 30-min i.v. infusion on days 1–5 of a 21-d cycle. Experience from a parallel dose-finding study in patients with solid tumors influenced the selection of the final dose. Results: 

Sixteen patients received belinostat at one of three dose levels: 600 mg/m2/d (three patients), 900 mg/m2/d (three patients) and 1000 mg/m2/d (10 patients), the dose determined to be the MTD in a phase I solid tumor study [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%) and flushing (31%). No grade 3 or 4 hematological toxicity compared with baseline occurred except one case of grade 3 lymphopenia. There were two related grade 4 adverse events of renal failure observed. Both events occurred in patients with multiple myeloma and had similar characteristics, i.e. an acute episode of decrease in renal function (pre-existing nephropathy in one patient), with a metabolic profile and decrease in tumor burden consistent with tumor lysis syndrome. No other related grade 4 events were noted. The only related grade 3 events noticed in more than one patient were fatigue and neurological symptoms (one patient had status epilepticus in association with uremia and one patient had paresthesia), all other related grade 3 events occurred in single patients. No cardiac events were noted.

No complete or partial remissions were noted in these heavily pre-treated (median of four prior regimens) patients. However, five patients, including two patients with diffuse large-cell lymphoma [including one patient with transformed chronic myelomcytic leukaemia (CLL)], two patients with CLL and one patient with multiple myeloma, achieved disease stabilization in of two to nine treatment cycles. Conclusions: 

Intravenous belinostat at 600, 900 and 1000 mg/m2/d is well tolerated by patients with hematological malignancies. The study was carried out in parallel to a similar dose-finding study in patients with solid tumors, in which the MTD was determined to be 1000 mg/m2/d days 1–5 in a 21-d cycle. This dose can also be recommended for phase II studies in patients with hematological neoplasms.
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Keywords: PXD101; belinostat; hematological neoplasias; histone deacetylase inhibitor

Document Type: Research Article

Affiliations: 1: Department of Hematology, Finsen Center, University Hospital Rigshospitalet, Copenhagen 2: Department of Hematology, Herlev Amtssygehus, Herlev 3: Topotarget, Symbion Science Park, Fruebjergvej, Copenhagen, Denmark 4: CuraGen Corporation, Branford, CT, USA

Publication date: September 1, 2008

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