title: Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms.
abstract: OBJECTIVE
  A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma).
  
  
  METHODS
  Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted.
  
  
  RESULTS
  Sixteen patients were treated. The MTD was established as 1.3 mg/m(2) for bortezomib and 30 mg/m(2) for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results.
  
  
  CONCLUSIONS
  The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively.
authors: Massey Cancer Center and the Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors: Beata
authors: B
authors: Holkova
authors: E Brent
authors: EB
authors: Perkins
authors: Viswanathan
authors: V
authors: Ramakrishnan
authors: Mary Beth
authors: MB
authors: Tombes
authors: Ellen
authors: E
authors: Shrader
authors: Neha
authors: N
authors: Talreja
authors: Martha D
authors: MD
authors: Wellons
authors: Kevin T
authors: KT
authors: Hogan
authors: G David
authors: GD
authors: Roodman
authors: Domenico
authors: D
authors: Coppola
authors: Loveleen
authors: L
authors: Kang
authors: Jana
authors: J
authors: Dawson
authors: Robert K
authors: RK
authors: Stuart
authors: Cody
authors: C
authors: Peer
authors: William D
authors: WD
authors: Figg
authors: Sarah
authors: S
authors: Kolla
authors: Austin
authors: A
authors: Doyle
authors: John
authors: J
authors: Wright
authors: Daniel M
authors: DM
authors: Sullivan
authors: John D
authors: JD
authors: Roberts
authors: Steven
authors: S
authors: Grant
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D017211:Treatment Failure
chemical_list: D001897:Boronic Acids; D005419:Flavonoids; D010880:Piperidines; D011719:Pyrazines; C077990:alvocidib; D000069286:Bortezomib