title: Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma.
abstract: BACKGROUND
  Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma.
  
  
  METHODS
  The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m² daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6).
  
  
  RESULTS
  Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths.
  
  
  CONCLUSIONS
  These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.
authors: Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Shlomit
authors: S
authors: Yust-Katz
authors: Diane
authors: D
authors: Liu
authors: Ying
authors: Y
authors: Yuan
authors: Vivien
authors: V
authors: Liu
authors: Sanghee
authors: S
authors: Kang
authors: Morris
authors: M
authors: Groves
authors: Vinay
authors: V
authors: Puduvalli
authors: Victor
authors: V
authors: Levin
authors: Charles
authors: C
authors: Conrad
authors: Howard
authors: H
authors: Colman
authors: Sigmonid
authors: S
authors: Hsu
authors: W K Alfred
authors: WK
authors: Yung
authors: Mark R
authors: MR
authors: Gilbert
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D015173:Supratentorial Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D003986:Dibenzocycloheptenes
chemical_list: D003606:Dacarbazine; D010880:Piperidines; D011725:Pyridines; D000077204:Temozolomide; C115354:lonafarnib; D003986:Dibenzocycloheptenes
keywords: farnesyltransferase inhibitor; glioblastoma; lonafarnib; recurrent; temozolomide
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