title: Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib.
abstract: BACKGROUND
  Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients.
  
  
  METHODS
  The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/day, plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively.
  
  
  RESULTS
  A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered.
  
  
  CONCLUSIONS
  The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jcortes@mdanderson.org
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: Charles
authors.initials: C
authors.lastname: Koller
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhu
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D017211:Treatment Failure; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D003986:Dibenzocycloheptenes
chemical_list: D001549:Benzamides; D000068877:Imatinib Mesylate; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; C115354:lonafarnib; D003986:Dibenzocycloheptenes