title: Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10 derivative, administered as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory cancer.
abstract: BACKGROUND
  TZT-1027 is a synthetic dolastatin 10 analog with antineoplastic properties in various cell lines and tumor xenografts. The purpose of this phase I study was to evaluate the safety and toxicity, maximum tolerated dose, pharmacokinetics and pharmacodynamics, clinical and metabolic antitumor activity of TZT-1027 when given as a 1-h intravenous infusion every 3 weeks in patients with refractory solid tumors.
  
  
  METHODS
  Patients had a histologically verified refractory tumor with measurable disease, were > or = 18 years old, had an Eastern Cooperative Oncology Group performance status <2 and adequate bone marrow, liver, renal and cardiac function. Dose-limiting toxicity was defined as platelets <25 x 10(9)/l, neutrophils <0.5 x 10(9)/l for >5 days, febrile neutropenia > or = 38.5 degrees C with grade 4 (National Cancer Institute-common toxicity criteria) neutropenia, or grade 3/4 non-hematological toxicity excluding nausea and vomiting. The last dose was the dose where > or = 2 out of six patients experienced dose-limiting toxicity in cycle one. The maximum tolerated dose was one dose level below with less than two of six patients with dose-limiting events.
  
  
  RESULTS
  Twenty-one non-selected, fully evaluable patients were enrolled. The majority were male (19) and the median age was 55 years (range 39-67). Dose levels of TZT-1027 ranged from 1.35 to 3.0 mg/m(2). The median number of cycles was two (range 1-4). Dose-limiting toxicities were observed in three patients at the 3.0 mg/m(2) dose level, including neutropenia, fatigue and a short lasting, reversible peripheral neurotoxic syndrome. The most common toxicities per patient were fatigue, anorexia, alopecia, nausea, constipation, leukopenia and neutropenia. Based on RECIST criteria, the best response was stable disease in seven patients. The pharmacokinetic evaluation revealed a T(1/2) of approximately 7 h and linear kinetics.
  
  
  CONCLUSIONS
  The recommended dose of TZT-1027 for the 3-weekly administration is 2.7 mg/m(2). Neutropenia, fatigue and a reversible peripheral neurotoxic syndrome are dose-limiting with this schedule. TZT-1027 may be associated with neurological side-effects in patients previously exposed to neurotoxic compounds such as oxaliplatin.
authors.affiliation: Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany. schoeffski.patrick@mh-hannover.de
authors.forename: P
authors.initials: P
authors.lastname: Schöffski
authors.forename: B
authors.initials: B
authors.lastname: Thate
authors.forename: G
authors.initials: G
authors.lastname: Beutel
authors.forename: O
authors.initials: O
authors.lastname: Bolte
authors.forename: D
authors.initials: D
authors.lastname: Otto
authors.forename: M
authors.initials: M
authors.lastname: Hofmann
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: A
authors.initials: A
authors.lastname: Jenner
authors.forename: P
authors.initials: P
authors.lastname: Cheverton
authors.forename: J
authors.initials: J
authors.lastname: Wanders
authors.forename: T
authors.initials: T
authors.lastname: Oguma
authors.forename: R
authors.initials: R
authors.lastname: Atsumi
authors.forename: M
authors.initials: M
authors.lastname: Satomi
mesh_terms: D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D003248:Constipation / Q000139:chemically induced; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D009842:Oligopeptides / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; C105791:soblidotin; C064570:dolastatin 10