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


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.
Department of Hematology, Finsen Center, University Hospital Rigshospitalet, Copenhagen, Denmark. peter.gimsing@rh.regionh.dk
Peter
P
Gimsing
Mads
M
Hansen
Lene M
LM
Knudsen
P
P
Knoblauch
Ib Jarle
IJ
Christensen
Chean Eng
CE
Ooi
Peter
P
Buhl-Jensen
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012074:Remission Induction; D013449:Sulfonamides; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C487081:belinostat