title: Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.
abstract: Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.
authors.affiliation: a Abramson Cancer Center , University of Pennsylvania, Perelman School of Medicine , Philadelphia , PA , USA.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Vogl
authors.affiliation: b Adult Leukemia and Bone Marrow Transplantation Program , University of California San Francisco , San Francisco , CA , USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Martin
authors.affiliation: c Bone Marrow Transplantation and Leukemia Section, Department of Medicine , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.affiliation: d Adult Blood and Marrow Transplant Program , Medical College of Wisconsin , Milwaukee , WI , USA.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
authors.affiliation: e Division of Hematology and Medical Oncology , Mayo Clinic , Scottsdale , AZ , USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mikhael
authors.affiliation: f John Theurer Cancer Center , Hackensack University Medical Center , Hackensack , NJ , USA.
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.affiliation: g Department of Hematology , ZNA Stuivenberg , Antwerp , Belgium.
authors.forename: Ka Lung
authors.initials: KL
authors.lastname: Wu
authors.affiliation: h Department of Hematology , University Hospital Leuven , Leuven , Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Delforge
authors.affiliation: i Division of Medicine-Cell Therapy and Hematologica , Duke University Medical Center , Durham , NC , USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gasparetto
mesh_terms: D000368:Aged; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D019233:Retreatment; D013912:Threonine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D013912:Threonine; C527966:delanzomib
keywords: CEP-18770; Delanzomib; phase I/II study; proteasome inhibitor; relapsed/refractory multiple myeloma