Phase I Pharmacokinetic and Pharmacodynamic Study of LAQ824, a Hydroxamate Histone Deacetylase Inhibitor with a Heat Shock Protein-90 Inhibitory Profile, in Patients with Advanced Solid Tumors

Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research , Surrey, UK.
Clinical Cancer Research (Impact Factor: 8.72). 11/2008; 14(20):6663-73. DOI: 10.1158/1078-0432.CCR-08-0376
Source: PubMed


To determine the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile of a histone deacetylase inhibitor, LAQ824, in patients with advanced malignancy. Patients and Methods: LAQ824 was administered i.v. as a 3-h infusion on days 1, 2, and 3 every 21 days. Western blot assays of peripheral blood mononuclear cell lysates and tumor biopsies pretherapy and posttherapy evaluated target inhibition and effects on heat shock protein-90 (HSP90) client proteins and HSP72.
Thirty-nine patients (22 male; median age, 53 years; median Eastern Cooperative Oncology Group performance status 1) were treated at seven dose levels (mg/m(2)): 6 (3 patients), 12 (4 patients), 24 (4 patients), 36 (4 patients), 48 (4 patients), 72 (19 patients), and 100 (1 patient). Dose-escalation used a modified continual reassessment method. Dose-limiting toxicities were transaminitis, fatigue, atrial fibrillation, raised serum creatinine, and hyperbilirubinemia. A patient with pancreatic cancer treated at 100 mg/m(2) died on course one at day 18 with grade 3 hyperbilirubinemia and neutropenia, fever, and acute renal failure. The area under the plasma concentration curve increased proportionally with increasing dose; median terminal half-life ranged from 8 to 14 hours. Peripheral blood mononuclear cell lysates showed consistent accumulation of acetylated histones posttherapy from 24 mg/m(2); higher doses resulted in increased and longer duration of pharmacodynamic effect. Changes in HSP90 client protein and HSP72 levels consistent with HSP90 inhibition were observed at higher doses. No objective response was documented; 3 patients had stable disease lasting up to 14 months. Based on these data, future efficacy trials should evaluate doses ranging from 24 to 72 mg/m(2).
LAQ824 was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition.

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    • "ECG changes, such as T-wave flattening or inversion were observed in multiple trials [62]. In the drug safety study with romidepsin (LAQ824) on 32 patients, two patients showed QTc prolongation >500 ms accompanied by non-symptomatic ST-T-wave changes and one patient developed atrial fibrillation which led to a stop of therapy [63]. The patients received a relatively high dosage of HDACi (up to 100 mg/m2). "
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    • "However, when used in monotherapy, HDAC inhibitors showed limited efficacy in various solid malignancies, including PDAC [3], [12], [13]. Indeed, LAQ824 or MS-275 have been evaluated in phase I clinical trials in solid cancers, including PDAC, without any objective clinical response [14], [15]. Alternatively, HDAC inhibitors have been used in combined therapy strategies [16], [17], with some combinations generating promising effects for human PDAC in vitro [18]–[21] or in experimental tumors [22]. "
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    • "Components of the JAK/STAT pathways are also susceptible to HDAC inhibition and could be considered as targets for HDI use in patients (see also Section 4.7). A phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor, indicated that Hsp90 client proteins including c- Raf as well as Hsp70 could act as surrogate markers in patients with solid tumours (de Bono et al., 2008). "
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