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

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Udai BanerjiFerry Alm Eskens

Abstract

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 p...Continue Reading

References

Jan 19, 2000·Nature·B D Strahl, C D Allis
May 18, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·William Kevin KellyVictoria M Richon
Aug 11, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Francis GilesKapil Bhalla
Feb 5, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nicola L SteeleJohann S DeBono
Apr 19, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lillian L SiuMichael A Carducci
Jun 27, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lia GoreS Gail Eckhardt
Oct 1, 2008·Cancer Letters·Olaf WittIna Oehme
Mar 18, 2009·Cancer Letters·Sriram BalasubramanianJoseph J Buggy
Jun 11, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michael Bots, Ricky W Johnstone
Oct 15, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Andrew A Lane, Bruce A Chabner
Aug 11, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sean J WhittakerYoun H Kim
Jun 28, 2011·Expert Opinion on Investigational Drugs·Erin M Bertino, Gregory A Otterson
Aug 26, 2010·Pharmaceuticals·Srividya SubramanianRichard L Piekarz

❮ Previous
Next ❯

Citations

Jun 12, 2013·Current Treatment Options in Oncology·Gregory M Cote, Edwin Choy
May 9, 2014·Epigenomics·Charlotte PawlynGareth J Morgan
Jun 26, 2014·Cancer Letters·Michael SchnekenburgerMarc Diederich
Jan 10, 2016·Journal of Translational Medicine·Jiaqi LiuFazhi Qi
Dec 23, 2015·Clinical Epigenetics·Clara NerviGiovanni Codacci-Pisanelli
Nov 8, 2015·Mayo Clinic Proceedings·Vinay Prasad, Andrae Vandross
Jul 22, 2014·British Journal of Pharmacology·Laia Simó-Riudalbas, Manel Esteller
Feb 11, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Mohammad Hojjat-Farsangi
Oct 30, 2012·Molecular Oncology·Angela NebbiosoLucia Altucci
Sep 25, 2016·Seminars in Oncology·Udai Banerji, Paul Workman
Jan 25, 2019·Current Topics in Medicinal Chemistry·Yan LiBin He
Nov 20, 2019·Cancers·Edurne San José-EnérizFelipe Prosper
Oct 12, 2019·Nature Reviews. Drug Discovery·Soufiane Boumahdi, Frederic J de Sauvage
Aug 6, 2019·Advanced Pharmaceutical Bulletin·Rehmat Jan, Gul-E-Saba Chaudhry
Oct 20, 2018·Current Medicinal Chemistry·Loredana CappellacciRiccardo Petrelli
Sep 1, 2020·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Mayank BansalDebojyoti Chakraborty
Sep 8, 2016·Cold Spring Harbor Perspectives in Medicine·Yixuan Li, Edward Seto
Dec 13, 2017·Archives of Pharmacal Research·Pusoon Chun
Oct 11, 2017·Annual Review of Pharmacology and Toxicology·Richard L Bennett, Jonathan D Licht
Jan 3, 2014·The Journal of Clinical Investigation·Alison C West, Ricky W Johnstone
Apr 17, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anne M NoonanSusan E Bates
Dec 18, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anthony W TolcherJohann S de Bono
Dec 3, 2020·Frontiers in Oncology·Donglu WuDa Liu
Feb 6, 2021·The FEBS Journal·Shengrui Feng, Daniel D De Carvalho
May 31, 2021·European Journal of Medicinal Chemistry·Antonino LauriaAnnamaria Martorana

❮ Previous
Next ❯

Related Concepts

Related Feeds

Atrial Fibrillation

Atrial fibrillation is a common arrhythmia that is associated with substantial morbidity and mortality, particularly due to stroke and thromboembolism. Here is the latest research.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.

Atrial Filbrillation

Atrial fibrillation refers to the abnormal heart rhythm characterized by rapid and irregular beating of the atria. Here is the latest research.

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.