A Phase I Study of Quisinostat (JNJ-26481585), an Oral Hydroxamate Histone Deacetylase Inhibitor with Evidence of Target Modulation and Antitumor Activity, in Patients with Advanced Solid Tumors

Abstract

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi).Experimental Design: In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two-stage accelerated titration design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th). Toxicity, pharmacokinetics, pharmacodynamics, and clinical efficacy were evaluated at each schedule.Results: Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy, and vomiting. DLTs observed were predominantly cardiovascular, including nonsustained ventricular tachycardia, ST/T-wave abnormalities, and other tachyarhythmias. Noncardiac DLTs were fatigue and abnormal liver function tests. The maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) of quisinostat increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies, and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting five months was seen in one patient with melanoma. Stable disease was seen in eight patients (duration 4-10.5 months).Conclusions: The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule. Clin Cancer Res; 19(15); 4262-72. Ó2013 AACR.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

“…A phase I clinical trial showed JNJ-26481585 to have a much greater plasma half-life of 8.8 hours in patients with advanced solid tumors compared to other HDAC inhibitors, such as vorinostat and romidepsin (49,50), and it shows promise for use in solid tumors either as a single agent or in combination with SOC (35). The dismal plight of those with advanced NSCLC and the observation here that even early-stage tumors are insensitive to current SOCs highlights the need for novel therapeutic or combinatorial options in this setting.…”

“…HDAC inhibitors induce apoptosis, cell-cycle arrest, and terminal differentiation in a variety of human tumors and, while currently only clinically licensed for hematological malignancies, show promise in solid tumors, including NSCLC (33). Three class I HDAC inhibitors-JNJ-26481585 (34,35), panobinostat, and vorinostat-were tested in the panel of patient-derived NSCLC specimens. Samples were classified as sensitive, if the IC 50 was below the achievable serum concentrations in humans (1.5 mmol/L panobinostat, 1.81 mmol/L vorinostat: see Supplementary Table S1); as this information was unavailable for JNJ-26481585, 1 mmol/L was arbitrarily set as the cutoff.…”

Prognostic implications ofFGFR1andMYCstatus in esophageal squamous cell carcinoma

“…FGFR1 amplification is considered an adequate factor to predict sensitivity to FGFR inhibitors[24]. However, FGFR inhibitors resulted in insufficient clinical responses in patients with FGFR1- amplified lung cancer[25,26]. A recent study showed that MYC expression might modulate the sensitivity of FGFR1- amplified pulmonary SCC to FGFR1 inhibitors[13].…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…In estrogen receptor-positive breast cancer, the combination of exemestane with entinostat improves median PFS to 4.3 months and median OS to 28.1 months, whereas median PFS and OS is 2.3 and 19.8 months, respectively, in the exemestane plus placebo group (139). Other HDAC inhibitors, such as ITF2357, CHR-3996, and JNJ-26481585, have been studied and show promising antitumor effect (140)(141)(142).…”