TY - JOUR
T1 - A first in human phase i study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma
AU - Gallerani, Elisa
AU - Zucchetti, Massimo
AU - Brunelli, Dario
AU - Marangon, Elena
AU - Noberasco, Cristina
AU - Hess, Dagmar
AU - Delmonte, Angelo
AU - Martinelli, Giovanni
AU - Böhm, Steffen
AU - Driessen, Christopher
AU - De Braud, Filippo
AU - Marsoni, Silvia
AU - Cereda, Roberta
AU - Sala, Federica
AU - D'Incalci, Maurizio
AU - Sessa, Cristiana
PY - 2013/1
Y1 - 2013/1
N2 - 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 21 d 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 1.8 mg/m2 where 2 out of 5 patients showed dose limiting toxicities. The maximum tolerated/recommended dose (MTD/RD) of 1.5 mg/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 ± 43.5 h. 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.
AB - 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 21 d 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 1.8 mg/m2 where 2 out of 5 patients showed dose limiting toxicities. The maximum tolerated/recommended dose (MTD/RD) of 1.5 mg/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 ± 43.5 h. 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.
KW - Bortezomib analogue
KW - Multiple myeloma
KW - Phase I
KW - Proteasome inhibitor
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U2 - 10.1016/j.ejca.2012.09.009
DO - 10.1016/j.ejca.2012.09.009
M3 - Article
C2 - 23058787
AN - SCOPUS:84872109533
VL - 49
SP - 290
EP - 296
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 2
ER -