title: Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.
abstract: BACKGROUND
  Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours.
  
  
  METHODS
  Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days.
  
  
  RESULTS
  On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers).
  
  
  CONCLUSIONS
  On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.
authors.affiliation: Department of Medical Oncology, City of Hope, Duarte, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Koczywas
authors.affiliation: Department of Information Sciences, City of Hope, Duarte, CA, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Frankel
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Synold
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Department of Medical Oncology, City of Hope, Duarte, CA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Mortimer
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: El-Khoueiry
authors.affiliation: Medical Center, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: Department of Medical Oncology, City of Hope, Duarte, CA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Cristea
authors.affiliation: Department of Medical Oncology, City of Hope, Duarte, CA, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Chung
authors.affiliation: Department of Medical Oncology, City of Hope, Duarte, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Medical Oncology, City of Hope, Duarte, CA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Reckamp
authors.affiliation: Medical Center, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Lau
authors.affiliation: Investigational Drug Research, National Cancer Institute, Rockville, MD, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: Department of Information Sciences, City of Hope, Duarte, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ruel
authors.affiliation: Department of Research-RN, City of Hope, Duarte, CA, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Carroll
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Newman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004988:Ethers, Cyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005663:Furans / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000009:adverse effects; D018942:Macrolides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D055815:Young Adult; D000095662:Polyether Polyketides
chemical_list: D002945:Cisplatin; D004988:Ethers, Cyclic; D005663:Furans; D007659:Ketones; D018942:Macrolides; C070519:halichondrin B; D000095662:Polyether Polyketides; C490954:eribulin