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. CONCLUSION: A causal relationship of observed thromboembolic events to CDDO was considered possible but could not be established.
BACKGROUND: The triterpenoid2-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. CONCLUSION: A causal relationship of observed thromboembolic events to CDDO was considered possible but could not be established.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: Som D Mukherjee; Megan E Coombes; Mitch Levine; Jarold Cosby; Brenda Kowaleski; Andrew Arnold Journal: Invest New Drugs Date: 2010-05-29 Impact factor: 3.850
Authors: M T Huang; C T Ho; Z Y Wang; T Ferraro; Y R Lou; K Stauber; W Ma; C Georgiadis; J D Laskin; A H Conney Journal: Cancer Res Date: 1994-02-01 Impact factor: 12.701
Authors: W-S Suh; Y S Kim; A D Schimmer; S Kitada; M Minden; M Andreeff; N Suh; M Sporn; J C Reed Journal: Leukemia Date: 2003-11 Impact factor: 11.528
Authors: Irene M Pedersen; Shinichi Kitada; Aaron Schimmer; Youngsoo Kim; Juan M Zapata; Lula Charboneau; Laura Rassenti; Michael Andreeff; Frank Bennett; Michael B Sporn; Lance D Liotta; Thomas J Kipps; John C Reed Journal: Blood Date: 2002-10-15 Impact factor: 22.113
Authors: Muthu K Shanmugam; Xiaoyun Dai; Alan Prem Kumar; Benny K H Tan; Gautam Sethi; Anupam Bishayee Journal: Cancer Lett Date: 2014-01-30 Impact factor: 8.679
Authors: Ben C Creelan; Dmitry I Gabrilovich; Jhanelle E Gray; Charles C Williams; Tawee Tanvetyanon; Eric B Haura; Jeffrey S Weber; Geoffrey T Gibney; Joseph Markowitz; Joel W Proksch; Scott A Reisman; Mark D McKee; Melanie P Chin; Colin J Meyer; Scott J Antonia Journal: Onco Targets Ther Date: 2017-08-29 Impact factor: 4.147