title: Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase I trial in patients with advanced solid tumors: a California Cancer Consortium trial.
abstract: BACKGROUND
  The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four.
  
  
  METHODS
  This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m(2), and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay.
  
  
  RESULTS
  Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m(2)/week. The second phase ended at 2.0 mg/m(2)/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m(2)/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]).
  
  
  CONCLUSIONS
  E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of β-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA. rmorgan@coh.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.affiliation: Department of Cancer Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.affiliation: Department of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Longmate
authors.affiliation: Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.affiliation: Division of Medical Oncology, University of California, Davis Cancer Center, Sacramento, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gandara
authors.affiliation: Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Department of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ruel
authors.affiliation: Department of Cancer Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
authors.forename: Bixin
authors.initials: B
authors.lastname: Xi
authors.affiliation: Eisai Research Institute, Andover, MA, 01810, USA.|Edward P. Evans Foundation, Casanova, VA, 20139, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lewis
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA.|Stanford Cancer Center, Stanford, CA, 94305, USA.
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.|Division of Cancer Treatment and Diagnosis6, National Cancer Institute, Bethesda, MD, 20892, USA.
authors.forename: James
authors.initials: J
authors.lastname: Doroshow
authors.affiliation: Department of Cancer Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Newman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D064147:Febrile Neutropenia / Q000139:chemically induced; D005260:Female; D005663:Furans / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007275:Injections, Intravenous; D007659:Ketones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy; D016879:Salvage Therapy; D050257:Tubulin Modulators / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014571:Urologic Neoplasms / Q000097:blood / Q000188:drug therapy; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; D050257:Tubulin Modulators; C490954:eribulin; D000095662:Polyether Polyketides
keywords: Eribulin; Halichondrin B analog; Pharmacodynamics; Pharmacokinetics; Phase I trial