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

Eur J Cancer. 2013 Jan;49(2):290-6. doi: 10.1016/j.ejca.2012.09.009. Epub 2012 Oct 8.


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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

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


  • Boronic Acids
  • Proteasome Inhibitors
  • Threonine
  • delanzomib