title: Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors.
abstract: BACKGROUND
  KRN5500, a novel spicamycin derivative, shows an inhibitory effect on protein synthesis. This phase I study was aimed at investigating the toxicity, maximum tolerated dose (MTD) and pharmacokinetics of this compound.
  
  
  METHODS
  Patients with solid tumors not amenable to standard forms of treatment were eligible. KRN5500 was administered as a 2 h intravenous infusion every 4 weeks at doses of 3, 6, 10, 15 and 21 mg/m(2). Pharmacokinetic evaluation was performed at the first cycle.
  
  
  RESULTS
  Eighteen patients with advanced solid tumors were enrolled. A total of 26 cycles of KRN5500 were administered. The major toxicities were nausea, vomiting, diarrhea, fatigue and a mild reversible prolongation of prothrombin time. Grade 4 pulmonary toxicity (interstitial pneumonitis) was observed in one patient at a dose level of 15 mg/m(2). Severe fatigue was observed in one patient at a dose level of 21 mg/m(2) and the duration of fatigue tended to increase with the dose of KRN5500. Nausea and vomiting were frequently observed and became prolonged with increasing dose of KRN5500. These toxicity profiles were identified as unacceptable and further dose escalation above 21 mg/m(2) was withheld. The MTD was therefore determined as 21 mg/m(2). The peak plasma concentration and the area under the concentration-time curve of KRN5500 increased proportionally to the dose, suggesting linear pharmacokinetics. No objective antitumor response was observed.
  
  
  CONCLUSIONS
  KRN5500, a structurally novel protein synthesis inhibitor, warrants further investigation to overcome these toxicity profiles and improve its efficacy.
authors.affiliation: Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kamiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ono
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kondoh
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008168:Lung / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011684:Purine Nucleosides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D014840:Vomiting, Anticipatory / Q000209:etiology
chemical_list: D011500:Protein Synthesis Inhibitors; D011684:Purine Nucleosides; C092296:KRN 5500