Reference Detail

Ref Type

Journal Article

PMID

(21831953)

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	17	19	2011 Oct 01	6313-21	Clin Cancer Res

URL

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.

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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

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