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

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...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2012-02, Vol.69 (2), p.431-438
Main Authors: Speranza, Giovanna, Gutierrez, Martin E., Kummar, Shivaani, Strong, John M., Parker, Robert J., Collins, Jerry, Yu, Yunkai, Cao, Liang, Murgo, Anthony J., Doroshow, James H., Chen, Alice
Format: Article
Language:English
Subjects:
Anorexia - chemically induced
Antineoplastic agents
Apoptosis - drug effects
Biological and medical sciences
Blood and lymphatic vessels
Cancer Research
Cardiology. Vascular system
Cell Survival - drug effects
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Half-Life
Humans
Immunoblotting
Infusions, Intravenous
Jurkat Cells
Male
Medical sciences
Medicine
Medicine & Public Health
Metabolic Clearance Rate
Middle Aged
Mucositis - chemically induced
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Nausea - chemically induced
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Oleanolic Acid - adverse effects
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - pharmacokinetics
Oleanolic Acid - therapeutic use
Oncology
Original Article
Pharmacology. Drug treatments
Pharmacology/Toxicology
Poly(ADP-ribose) Polymerases - metabolism
Thromboembolism - chemically induced
Treatment Outcome
Tumors
Vomiting - chemically induced
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Summary: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.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-011-1712-y