title: Phase I trial of bortezomib (PS-341; NSC 681239) and "nonhybrid" (bolus) infusion schedule of alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms.
abstract: OBJECTIVE
  This 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, Waldenstrom macroglobulinemia, and mantle cell lymphoma).
  
  
  METHODS
  Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted.
  
  
  RESULTS
  A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses.
  
  
  CONCLUSIONS
  The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies.
authors.affiliation: Massey Cancer Center and Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. bholkova@mcvh-vcu.edu.
authors.forename: Beata
authors.initials: B
authors.lastname: Holkova
authors.affiliation: Massey Cancer Center and.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.affiliation: Massey Cancer Center and Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: E Brent
authors.initials: EB
authors.lastname: Perkins
authors.affiliation: Massey Cancer Center and Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Bose
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Rachid C
authors.initials: RC
authors.lastname: Baz
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Stuart
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Ramakrishnan
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Wen
authors.initials: W
authors.lastname: Wan
authors.affiliation: Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Jana
authors.initials: J
authors.lastname: Dawson
authors.affiliation: James A. Haley Veterans' Hospital, Tampa, Florida.
authors.forename: Loveleen
authors.initials: L
authors.lastname: Kang
authors.affiliation: Massey Cancer Center and.
authors.forename: Connie
authors.initials: C
authors.lastname: Honeycutt
authors.affiliation: Massey Cancer Center and.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Tombes
authors.affiliation: Massey Cancer Center and.
authors.forename: Ellen
authors.initials: E
authors.lastname: Shrader
authors.affiliation: Massey Cancer Center and.
authors.forename: Caryn
authors.initials: C
authors.lastname: Weir-Wiggins
authors.affiliation: Massey Cancer Center and.
authors.forename: Martha
authors.initials: M
authors.lastname: Wellons
authors.affiliation: Massey Cancer Center and.
authors.forename: Heidi
authors.initials: H
authors.lastname: Sankala
authors.affiliation: Massey Cancer Center and.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Hogan
authors.affiliation: Cancer Therapy Evaluation Program, NCI, NIH, Bethesda, Maryland. Departments of.
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.affiliation: Cancer Therapy Evaluation Program, NCI, NIH, Bethesda, Maryland. Departments of.
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Massey Cancer Center and Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: John D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.affiliation: Massey Cancer Center and Massey Cancer Center and Massey Cancer Center and Massey Cancer Center and Massey Cancer Center and.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000473:pathology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D000069286:Bortezomib; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D012008:Recurrence; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D005419:Flavonoids; D010880:Piperidines; D011719:Pyrazines; C077990:alvocidib; D000069286:Bortezomib