title: Phase I trial of vinflunine and pemetrexed in refractory solid tumors.
abstract: BACKGROUND
  Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors.
  
  
  METHODS
  A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500 mg/m(2) was given with vinflunine 280 mg/m(2) (cohort 1), 300 mg/m(2) (cohort 2) or 320 mg/m(2) (cohort 3) on day 1 of a 21-day cycle.
  
  
  RESULTS
  19 patients were enrolled, median age 58 years (range 32 to 77) and had a median of 3 (range 1-6) prior therapies. DLT occurred 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively.
  
  
  CONCLUSIONS
  Based on this experience we recommend vinflunine 300 mg/m(2) and pemetrexed 500 mg/m(2) in combination every 3 weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. hsanoff@virginia.edu
authors.forename: Hanna K
authors.initials: HK
authors.lastname: Sanoff
authors.forename: Janine
authors.initials: J
authors.lastname: Davies
authors.forename: Christine
authors.initials: C
authors.lastname: Walko
authors.forename: Larry
authors.initials: L
authors.lastname: Buie
authors.forename: Wing-Keung
authors.initials: WK
authors.lastname: Chiu
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.forename: Bert
authors.initials: B
authors.lastname: O'Neil
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Stinchcombe
authors.forename: Kimberly
authors.initials: K
authors.lastname: Keller
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000068437:Pemetrexed; D010641:Phenotype; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; C111217:vinflunine; D014747:Vinblastine; D006147:Guanine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam