Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors

Abstract

Background The triterpenoid 2-Cyano-3, 12-Dioxoolean-1, 9-Dien-28-Oic Acid (CDDO, previously RTA-401) is a multifunctional molecule that controls cellular growth and differentiation. It is capable of activating the transcription factor peroxisome proliferator activator receptor-γ (PPARγ) and inducing apoptosis in malignant cells in vitro and in vivo. We conducted a phase I dose-escalation study to determine the toxicity, the maximum tolerated dose, and the pharmacokinetics and pharmacodynamics of CDDO, administered as a 5-day continuous infusion every 28 days in patients with advanced cancers. Methods An accelerated titration design was followed, with one patient per cohort entered, and doses ranging from 0.6 mg/m2/hr to 38.4 mg/m2/hr. Pharmacokinetics of CDDO was assessed and cleaved poly (ADP-ribose) polymerase (c-PARP), as a marker of apoptosis, was measured in peripheral blood mononuclear cells to assess drug effect. Results Seven patients, one patient per dose level up to dose level 7 (38.4 mg/m2/hr), were enrolled and received a total of 11 courses of treatment. Cmax increased proportionally with dose. Preclinically determined efficacious blood level (1 μM) of drug was attained at the highest dose level. One patient, at dose level 6, experienced grade 2 mucositis, nausea, vomiting, and anorexia. Four patients, on different dose levels, developed thromboembolic events subsequently considered as dose-limiting toxicity. No anti-tumor activity was noted. Conclusion A causal relationship of observed thromboembolic events to CDDO was considered possible but could not be established. Because of the adverse events and the development of an orally bioavailable derivative compound, CDDO methyl ester, this trial was terminated.

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

“…gov/ct2/show/NCT00322140). CDDO was given to seven patients by continuous infusion (0.6 -38.4 mg/m 2 per hour) for 5 days in 28-day cycles to determine the maximum tolerated dose, toxicity, and pharmacokinetics and pharmacodynamics of the drug (Speranza et al, 2012). Plasma concentrations of CDDO above 1 M, the target blood level determined in preclinical studies, were achieved in only a single patient.…”

Cytoprotection of Human Endothelial Cells from Oxidant Stress with CDDO Derivatives: Network Analysis of Genes Responsible for Cytoprotection

“…In addition, they have been shown to provide a chemopreventive effect against certain tumors, largely by reducing the viability of these cells [6,7,8]. How drugs can be cytoprotective in normal cells and cytotoxic in tumors and tumor-derived cells is not immediately clear.…”

A preliminary evaluation of bardoxolone methyl for the treatment of diabetic nephropathy

“…No adverse toxicity was reported. In a second published study, escalating doses of CDDO were administered as a 5-day continuous infusion every 28 days in seven patients with advanced refractory cancer, using a Simon accelerated titration design with an initial starting dose of 0.6 mg/m 2 /h and dosing up to 38.4 mg/m 2 /h [18]. All patients completed at least the first course of treatment.…”