title: A phase I clinical-pharmacodynamic study of the farnesyltransferase inhibitor tipifarnib in combination with the proteasome inhibitor bortezomib in advanced acute leukemias.
abstract: OBJECTIVE
  To determine the safety, target inhibition, and signals of clinical activity of tipifarnib in combination with bortezomib in patients with advanced acute leukemias.
  
  
  METHODS
  In a "3 + 3" design, patients received escalating doses of tipifarnib (days 1-14) and bortezomib (days 1, 4, 8, 11) every 3 weeks until maximum tolerated dose was reached. Peripheral blood mononuclear cells (PBMC) were collected at days 1, 8, and 22 for measurement of chymotrypsin-like and farnesyltransferase activity. Purified bone marrow leukemic blasts were collected at baseline and at day 8 for measurement of NF-κB activity.
  
  
  RESULTS
  The combination was well-tolerated, and maximum tolerated dose was not reached. Dose-limiting toxicities included diarrhea, fatigue, and sensorimotor neuropathy. Chymotrypsin-like and farnesyltransferase activity within PBMCs were decreased in a majority of patients at day 8. NF-κB activity within leukemic blasts was decreased in a majority of patients at day 8. Complete response with incomplete count recovery was observed in 2 patients, and additional 5 patients had stable disease.
  
  
  CONCLUSIONS
  Tipifarnib and bortezomib combination in patients with advanced leukemias was well-tolerated, demonstrated relevant target inhibition, and was associated with signals of clinical activity in patients with advanced and refractory acute leukemias. Future studies of this combination may be warranted in more selected groups of patients in whom these molecular targets are of particular importance.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. jeffrey.lancet@moffitt.org
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.forename: Vu H
authors.initials: VH
authors.lastname: Duong
authors.forename: Elliott F
authors.initials: EF
authors.lastname: Winton
authors.forename: Robert K
authors.initials: RK
authors.lastname: Stuart
authors.forename: Michelle
authors.initials: M
authors.lastname: Burton
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Christopher
authors.initials: C
authors.lastname: Cubitt
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D002918:Chymotrypsin / Q000097:blood / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000097:blood; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D015363:Quinolones; D000069286:Bortezomib; D051231:Farnesyltranstransferase; D002918:Chymotrypsin; C402769:tipifarnib