TY - JOUR
T1 - Phase i study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors
AU - Speranza, Giovanna
AU - Gutierrez, Martin E.
AU - Kummar, Shivaani
AU - Strong, John M.
AU - Parker, Robert J.
AU - Collins, Jerry
AU - Yu, Yunkai
AU - Cao, Liang
AU - Murgo, Anthony J.
AU - Doroshow, James H.
AU - Chen, Alice
PY - 2012/2
Y1 - 2012/2
N2 - 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/m2/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.
AB - 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/m2/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.
KW - Adverse event
KW - CDDO
KW - Thromboembolism
KW - Triterpenoid
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U2 - 10.1007/s00280-011-1712-y
DO - 10.1007/s00280-011-1712-y
M3 - Article
C2 - 21805353
AN - SCOPUS:84856746969
SN - 0344-5704
VL - 69
SP - 431
EP - 438
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -