title: Phase I and pharmacokinetic study of anhydrovinblastine every 3 weeks in patients with refractory solid tumors.
abstract: OBJECTIVE
  Anhydrovinblastine (AVLB) is a novel semisynthetic vinca alkaloid. We conducted a phase I trial to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacokinetics of AVLB given as a 1-h intravenous infusion once every 3 weeks in patients with advanced refractory solid tumors.
  
  
  METHODS
  Entered into the study were 24 patients with normal bone marrow, hepatic and renal function, and of these 21 were evaluable. There were 12 males and 12 females with a median age of 60 years (range 27-75 years). Diagnoses were non-small-cell lung cancer (NSCLC) (11), colorectal cancer (5), soft tissue sarcoma (4), and miscellaneous (4). Patients had had a median of three prior chemotherapy regimens (range one to six). A total of 51 courses were administered at doses of 2.5, 5, 10, 16.5, 21, 25 and 30 mg/m(2) in one, three, one, three, six, six and one patient respectively.
  
  
  RESULTS
  Grade 2 infusional hypertension, anemia, and dizziness were noted at 16.5 mg/m(2). At 25 mg/m(2), two of six evaluable patients had DLT. DLT was grade 4 constipation, neutropenia and grade 3 nausea/vomiting. At 21 mg/m(2) one of six evaluable patients had DLT (grade 3 nausea/vomiting). This dose was the MTD. Stable disease was noted in one patient with metastatic sarcoma to the lungs and in three patients with metastatic NSCLC. The pharmacokinetics of AVLB were linear, and well characterized by a two-compartment model, with a mean clearance of 26.4 l/h per m(2) and median terminal half-life of 18 h.
  
  
  CONCLUSIONS
  The recommended phase II dose is 21 mg/m(2). A phase II study in NSCLC is being initiated.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. nithya.ramnath@roswellpark.org
authors.forename: Nithya
authors.initials: N
authors.lastname: Ramnath
authors.forename: Gary N
authors.initials: GN
authors.lastname: Schwartz
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Daniel
authors.initials: D
authors.lastname: Bong
authors.forename: Peter
authors.initials: P
authors.lastname: Kanter
authors.forename: Joanne
authors.initials: J
authors.lastname: Berdzik
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Creaven
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; C056817:3',4'-anhydrovinblastine; D014747:Vinblastine