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

• Published in: Clinical cancer research 2011-10, Vol.17 (19), p.6313-6321
• Main Authors: TABERNERO, Josep, DIRIX, Luc, KNOBLAUCH, Roland, ZHUANG, Sen Hong, SCHÖFFSKI, Patrick, CERVANTES, Andres, LOPEZ-MARTIN, Jose Antonio, CAPDEVILA, Jaume, VAN BEIJSTERVELDT, Ludy, PLATERO, Suso, HALLS, Brett, ZHILONG YUAN
• Format: Article
• Language: English
• Subjects: Administration, Oral; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Pharmacology. Drug treatments; Tryptamines - adverse effects; Tryptamines - pharmacokinetics; Tryptamines - therapeutic use; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-1101

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.