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|Ref Type||Journal Article|
|Authors||Tabernero J, Dirix L, Schöffski P, Cervantes A, Lopez-Martin JA, Capdevila J, van Beijsterveldt L, Platero S, Hall B, Yuan Z, Knoblauch R, Zhuang SH|
|Title||A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2011 Oct 01|
|Abstract Text||Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose.Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction.The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (C(max)) was 2,330 ng/mL and mean area under plasma concentration curve (AUC(0-24h)) was 43.0 μg.h/mL, with serdemetan 300 mg/d. There was a dose- and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease.Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|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|
|TP53 positive||breast cancer||sensitive||Serdemetan||Phase I||Actionable||In a Phase I trial, Serdemetan (JNJ-26854165) treatment induced a 102% increase of Tp53 expression in tumor tissue, resulted in partial response in a patient with breast cancer (PMID: 21831953).||21831953|
|TP53 positive||Advanced Solid Tumor||sensitive||Serdemetan||Phase I||Actionable||In a Phase I trial, Serdemetan (JNJ-26854165) treatment increased Tp53 expression in tumor and surrogate tissue, resulted in partial response in 1.8% (1/57) and stable disease in 38.6% (22/57) of patients with advanced solid tumors (PMID: 21831953).||21831953|