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01.02.2012 | Original Article

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

verfasst von: Giovanna Speranza, Martin E. Gutierrez, Shivaani Kummar, John M. Strong, Robert J. Parker, Jerry Collins, Yunkai Yu, Liang Cao, Anthony J. Murgo, James H. Doroshow, Alice Chen

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2012

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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/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/m²/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.

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Titel: Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors
verfasst von: Giovanna Speranza
Martin E. Gutierrez
Shivaani Kummar
John M. Strong
Robert J. Parker
Jerry Collins
Yunkai Yu
Liang Cao
Anthony J. Murgo
James H. Doroshow
Alice Chen
Publikationsdatum: 01.02.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2012
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1712-y

Springer Medizin

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