title: A phase I pharmacokinetic study of PM00104 (Zalypsis) administered as a 24-h intravenous infusion every 3 weeks in patients with advanced solid tumors.
abstract: OBJECTIVE
  PM00104 (Zalypsis) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk).
  
  
  METHODS
  Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 + 3 patients per cohort). Plasma samples were collected for PK analysis.
  
  
  RESULTS
  DLTs comprised severe neutropenia lasting >5 days (n = 4 patients), vomiting, thrombocytopenia, transaminase increases (n = 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay >2 weeks due to moderate fatigue (n = 1 each). The RD was 4.0 mg/m(2). Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease ≥3 months.
  
  
  CONCLUSIONS
  PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed.
authors: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
authors: J
authors: J
authors: Capdevila
authors: S
authors: S
authors: Clive
authors: E
authors: E
authors: Casado
authors: C
authors: C
authors: Michie
authors: A
authors: A
authors: Piera
authors: E
authors: E
authors: Sicart
authors: M J
authors: MJ
authors: Carreras
authors: C
authors: C
authors: Coronado
authors: C
authors: C
authors: Kahatt
authors: A
authors: A
authors: Soto Matos-Pita
authors: C
authors: C
authors: Fernandez Teruel
authors: M
authors: M
authors: Siguero
authors: M
authors: M
authors: Cullell-Young
authors: J
authors: J
authors: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012720:Severity of Illness Index; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C500383:PM 00104; D044005:Tetrahydroisoquinolines