A Phase I First-in-Human Pharmacokinetic and Pharmacodynamic Study of Serdemetan in Patients with Advanced Solid Tumors

Abstract

Purpose: 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 and Methods: Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3þ3 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.Results: 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 mg.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.Conclusions: 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.

The re-emergence of natural products for drug discovery in the genomics era

“…Now known as RG7112 or RO5045337, it has completed Phase I trials in various cancers, but has not yet progressed further 245 . A tryptaminederived compound (JNJ-26854165, also known as serdemetan) has also been in Phase I trials in patients with solid, refractory tumours 246 . This compound had previously been shown to be active in several in vivo cancer models and has more recently been found to inhibit cholesterol transport in cancer-cell lines 247 , an action that might contribute to its anticancer activity in vivo.…”

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

“…Therefore, one of the main targets for cancer therapy is inhibition of the p53TAD-MDM2/MDMX interaction via the small molecule MDM2 antagonist that stabilizes p53 by blocking its interaction with MDM2 and selectively induces senescence in cancer cells (IancuRubin et al, 2014). Some of these small molecule MDM2 inhibitors such as R7112 (Nutlin-3, analogues of cisimidazoline) and JNJ-26854165 (a tryptamine derivative) are currently under clinical assessment in phase I studies (Tabernero et al, 2011;Shaomeng Wang et al, 2012;Sosin et al, 2012). In addition, Jae-sun Shin et al have shown that a p53TAD-mimetic MDM2 antagonist, R7112, can directly interact with BH3 peptide-binding grooves of diverse anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl-xL, Mcl-1 and Bcl-w in an analogous mode (Shin et al, 2012b;Shin et al, 2014).…”

Emerging therapies targeting the ubiquitin proteasome system in cancer

“…Many compounds, including serdemetan, nutlin-3 (RO5045337), and NSC-207895 all demonstrate in vitro anticancer activity (35)(36)(37). Serdemetan was tested in a phase I trial, with p53 induction seen, but cardiac conduction defects were observed (38). Nutlin-3 may be a promising agent and is registered for phase I trials for an array of malignancies (NCT00559533, NCT00623870), but these studies have not been published.…”