title: Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma.
abstract: OBJECTIVE
  Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro. We sought to test the combination clinically.
  
  
  METHODS
  A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.3 mg/m2 i.v. on days 1, 4, 8, and 11 and vorinostat at 100 to 500 mg orally daily for 8 days of each 21-day cycle in relapsed/refractory multiple myeloma patients. Vorinostat pharmacokinetics and dynamics were assessed.
  
  
  RESULTS
  Twenty-three patients were treated. Patients had received a median of 7 prior regimens (range, 3-13), including autologous transplantation in 20, thalidomide in all 23, lenalidomide in 17, and bortezomib in 19, 9 of whom were bortezomib-refractory. Two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common grade >3 toxicities were myelo-suppression (n = 13), fatigue (n = 11), and diarrhea (n = 5). There were no drug-related deaths. Overall response rate was 42%, including three partial responses among nine bortezomib refractory patients. Vorinostat pharmacokinetics were nonlinear. Serum Cmax reached a plateau above 400 mg. Pharmacodynamic changes in CD-138+ bone marrow cells before and on day 11 showed no correlation between protein levels of NF-kappaB, IkappaB, acetylated tubulin, and p21CIP1 and clinical response.
  
  
  CONCLUSIONS
  The maximum tolerated dose of vorinostat in our study was 400 mg daily for 8 days every 21 days, with bortezomib administered at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. The promising antimyeloma activity of the regimen in refractory patients merits further evaluation.
authors: University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland 21201, USA. Abadros@umm.edu
authors: Ashraf
authors: A
authors: Badros
authors: Angelika M
authors: AM
authors: Burger
authors: Sunita
authors: S
authors: Philip
authors: Ruben
authors: R
authors: Niesvizky
authors: Sarah S
authors: SS
authors: Kolla
authors: Olga
authors: O
authors: Goloubeva
authors: Carolynn
authors: C
authors: Harris
authors: James
authors: J
authors: Zwiebel
authors: John J
authors: JJ
authors: Wright
authors: Igor
authors: I
authors: Espinoza-Delgado
authors: Maria R
authors: MR
authors: Baer
authors: Julianne L
authors: JL
authors: Holleran
authors: Merrill J
authors: MJ
authors: Egorin
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; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D000077337:Vorinostat
chemical_list: D001897:Boronic Acids; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib