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

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/m(2)/d (three patients), 900 mg/m(2)/d (three patients) and 1000 mg/m(2)/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 myelocytic 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/m(2)/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/m(2)/d days 1-5 in a 21-d cycle. This dose can also be recommended for phase II studies in patients with hematological neoplasms.

• Authors: Peter Gimsing, Mads Hansen, Lene M Knudsen, P Knoblauch, Ib Jarle Christensen, Chean Eng Ooi, Peter Buhl-Jensen
• Journal: European journal of haematology (Eur J Haematol) Vol. 81 Issue 3 Pg. 170-6 (Sep 2008) ISSN: 1600-0609 [Electronic] England
• PMID: 18510700 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Sulfonamides
• belinostat

Topics

• Aged
• Antineoplastic Agents (administration & dosage, adverse effects)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug-Related Side Effects and Adverse Reactions
• Enzyme Inhibitors (administration & dosage, adverse effects)
• Female
• Hematologic Neoplasms (drug therapy)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects)
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Remission Induction
• Sulfonamides
• Time Factors
• Treatment Outcome