A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma.

Abstract

BACKGROUND:

The safety, pharmacokinetics (PK) and pharmacodynamics of CEP-18770, a new peptide boronic acid proteasome inhibitor, have been investigated after intravenous administration on days 1, 4, 8 and 11 of every 21d cycle in patients with solid tumours and multiple myeloma (MM).

PATIENTS AND METHODS:

Thirty-eight patients were treated with CEP-18770 at escalating doses from 0.1 to 1.8mg/m(2) where 2 out of 5 patients showed dose limiting toxicities. The maximum tolerated/recommended dose (MTD/RD) of 1.5mg/m(2) was tested in 12 additional patients. Skin rash was dose-limiting and occurred in 53% of patients; other frequent toxicities were asthenia (29%), stomatitis (21%) and pyrexia (16%). No significant peripheral neuropathy was observed. PK in plasma was linear with a half-life of the elimination phase of 62.0±43.5h. Proteasome inhibition in peripheral blood mononuclear cells was dose related in MM patients; it was of 45.4±11.5% at the RD.

CONCLUSIONS:

CEP-18770 showed a favourable safety profile with lack of neurotoxicity and linear plasma PK. The definition of the optimal biological dose and schedule of treatment is actively pursued because of the high incidence of skin toxicity of the twice a week schedule.

• Authors: Elisa Gallerani, Massimo Zucchetti, Dario Brunelli, Elena Marangon, Cristina Noberasco, Dagmar Hess, Angelo Delmonte, Giovanni Martinelli, Steffen Böhm, Christopher Driessen, Filippo De Braud, Silvia Marsoni, Roberta Cereda, Federica Sala, Maurizio D'Incalci, Cristiana Sessa
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 49 Issue 2 Pg. 290-6 (Jan 2013) ISSN: 1879-0852 [Electronic] England
• PMID: 23058787 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Boronic Acids
• Proteasome Inhibitors
• Threonine
• delanzomib

Topics

• Adult
• Aged
• Boronic Acids (adverse effects, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Multiple Myeloma (drug therapy, pathology)
• Neoplasms (drug therapy, pathology)
• Proteasome Inhibitors (adverse effects, therapeutic use)
• Threonine (adverse effects, analogs & derivatives, therapeutic use)