Reference Detail

Ref Type

Journal Article

PMID

(22553374)

Authors

Banerji U, van Doorn L, Papadatos-Pastos D, Kristeleit R, Debnam P, Tall M, Stewart A, Raynaud F, Garrett MD, Toal M, Hooftman L, De Bono JS, Verweij J, Eskens FA

Title

A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	18	9	2012 May 01	2687-94	Clin Cancer Res

URL

Abstract Text

This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation 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.Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The dose-limiting 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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CHR-3996	CHR-3996	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CHR-3996		VRx3996\|Tractinostat\|Nanatinostat	HDAC Inhibitor 45	Tractinostat (CHR-3996) is a selective Class I HDAC inhibitor, which may result in decreased tumor growth (PMID: 22553374).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References