A Phase I Pharmacokinetic and Pharmacodynamic Study of CHR-3996, an Oral Class I Selective Histone Deacetylase Inhibitor in Refractory Solid Tumors

Abstract

Purpose: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.Patients and Methods: CHR-3996 was administered orally once a day. This phase I trial used a 3þ3 doseescalation design. PK profiles were analyzed by liquid chromatography-tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells.Results: Thirty-nine patients were treated at dose levels of 5 mg (n ¼ 3), 10 mg (n ¼ 4), 20 mg (n ¼ 3), 40 mg (n ¼ 10), 80 mg (n ¼ 10), 120 mg (n ¼ 4), and 160 mg (n ¼ 5) administered orally once daily. The doselimiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma.Conclusions: Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials.

Antitumor Activity in RAS-Driven Tumors by Blocking AKT and MEK

“…Rash was the most frequent adverse event and DLT; two distinct appearances were noted: a reversible maculopapular rash associated with pruritus consistent with our previous experience with MK-2206 (17); and an erythematous acneiform rash associated with selumetinib that improved with topical steroids or oral tetracycline therapy (24). Other DLT included diarrhoea and stomatitis, which appeared to be dose-related.…”

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

“…Among 14 evaluable phase I patients, 2 out of 5 patients with PDAC showed partial response with tumour shrinking and 1 patient had stable disease (American Society of Clinical Oncology Meeting 2008, abstract 4625). In contrast to these results that suggest synergism of the gemcitabine/HDACi combination in patients with PDAC,39 the majority of studies revealed restricted effects in a limited number of patients with distinct histological PDAC subgroups40 41 or even characterised combination with HDACi to be inferior to gemcitabine monotherapy in this tumour entity (NCT00004861) 42…”

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).…”