title: A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours.
abstract: BACKGROUND
  Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells.
  
  
  METHODS
  We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC.
  
  
  RESULTS
  No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug-drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1-6.6).
  
  
  CONCLUSIONS
  This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.
authors.affiliation: 1] Department of Medical Oncology, Centre Oscar Lambret, 3, rue F Combemale, Lille, France [2] Catholic University of Lille, Medical School, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Adenis
authors.forename: I
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: A
authors.initials: A
authors.lastname: Italiano
authors.forename: E
authors.initials: E
authors.lastname: Chauzit
authors.forename: B
authors.initials: B
authors.lastname: Bui-Nguyen
authors.forename: J-Y
authors.initials: JY
authors.lastname: Blay
authors.forename: E
authors.initials: E
authors.lastname: Tresch-Bruneel
authors.forename: C
authors.initials: C
authors.lastname: Fournier
authors.forename: S
authors.initials: S
authors.lastname: Clisant
authors.forename: E Y
authors.initials: EY
authors.lastname: Amela
authors.forename: P A
authors.initials: PA
authors.lastname: Cassier
authors.forename: M
authors.initials: M
authors.lastname: Molimard
authors.forename: N
authors.initials: N
authors.lastname: Penel
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002817:Chordoma / Q000188:drug therapy; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012878:Skin Neoplasms / Q000188:drug therapy
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide