title: 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. While CDDO is capable of activating the transcription factor peroxisome proliferator activator receptor-γ (PPARγ), its apoptotic effects in malignant cells have been shown to occur independently of PPARγ. A phase I dose-escalation study was conducted 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 to 38.4 mg/m(2)/h. 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/m(2)/h), 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 developed thromboembolic events subsequently considered as dose-limiting toxicity. No antitumor activity was noted.
  
  
  CONCLUSIONS
  A causal relationship of observed thromboembolic events to CDDO was considered possible but could not be established.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Speranza
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gutierrez
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: John M
authors.initials: JM
authors.lastname: Strong
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Parker
authors.forename: Jerry
authors.initials: J
authors.lastname: Collins
authors.forename: Yunkai
authors.initials: Y
authors.lastname: Yu
authors.forename: Liang
authors.initials: L
authors.lastname: Cao
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
mesh_terms: D000855:Anorexia / Q000139:chemically induced; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D015151:Immunoblotting; D007262:Infusions, Intravenous; D019169:Jurkat Cells; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009828:Oleanolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013923:Thromboembolism / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D009828:Oleanolic Acid; D011065:Poly(ADP-ribose) Polymerases