title: Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies.
abstract: OBJECTIVE
  Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound.
  
  
  METHODS
  Two centers contributed 25 patients to the trial, and 7 dose levels were explored.
  
  
  RESULTS
  In dose levels ranging from 4 to 128 mg/m²/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/m², a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/m² for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (<3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent.
  
  
  CONCLUSIONS
  Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials.
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium. patrick.schoffski@uzleuven.be
authors.forename: P
authors.initials: P
authors.lastname: Schöffski
authors.forename: H
authors.initials: H
authors.lastname: Dumez
authors.forename: R
authors.initials: R
authors.lastname: Ruijter
authors.forename: B
authors.initials: B
authors.lastname: Miguel-Lillo
authors.forename: A
authors.initials: A
authors.lastname: Soto-Matos
authors.forename: V
authors.initials: V
authors.lastname: Alfaro
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008055:Lipids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; C408363:spisulosine