title: Broad spectrum preclinical antitumor activity of eribulin (Halaven(R)): optimal effectiveness under intermittent dosing conditions.
abstract: BACKGROUND
  Eribulin is a pharmaceutically and structurally optimized analog of the marine sponge natural product halichondrin B. Its salt form, eribulin mesylate (Halaven®) is clinically used in the United States, the European Union, and Japan for the treatment of heavily pretreated patients with metastatic breast cancer, who previously received an anthracycline and a taxane. Early preclinical studies of this new inhibitor of microtubule dynamics showed high antitumor potency towards several human cancer types in vitro and in vivo. Here we extend those early studies by examining the effects of eribulin against a wider spectrum of human tumor xenografts in vivo, and by directly comparing the in vivo effectiveness of different dosing administration schedules.
  
  
  METHODS
  In single-schedule studies, in vivo activity of eribulin against HT-1080 fibrosarcoma, U251 glioblastoma, SR-475 head and neck cancer, SK-LMS-1 leiomyosarcoma, NCI-H322M and NCI-H522 non-small cell lung cancer (NSCLC), PANC-1 pancreatic cancer, and NCI-H82 small cell lung cancer (SCLC) xenografts was examined at dose levels of 0.19-4.0 mg/kg using q2d×3(×3), q4d×3, q4d×4, and q7d×2 schedules. Administration schedule dependence was evaluated by directly comparing q1d×5, q2d×3(×3), q4d×3, and q7d×3 schedules in the MDA-MB-435 breast cancer xenograft model, using conditions of equivalent total dosing over the course of the experiment.
  
  
  RESULTS
  In single-schedule studies, maximum tolerated dose (MTD) values (or maximal 'at or below MTD' values) ranged from 0.8-1.7 mg/kg. In vivo antitumor responses at these dosing levels included tumor growth inhibition, stasis, and regression; several studies showing regression also yielded long-term tumor-free survivors. Effectiveness of eribulin showed model-to-model variability that appeared to be unrelated to dose level or administration schedule, suggesting that characterization of models with differing eribulin sensitivities may reveal potential biomarker strategies. Results of the dose schedule comparison study in the MDA-MB-435 model suggested the following order of effectiveness and tolerability: q2d×3(×3)>q4d×3≈q7d×3>> q1d×5. Moderately intermittent dosing thus shows optimal preclinical effectiveness, in good agreement with the approved intermittent clinical schedule for eribulin (days 1 and 8 of a 21-day cycle).
  
  
  CONCLUSIONS
  The current results show that eribulin has broad spectrum preclinical antitumor activity against a wide variety of human cancer types, and indicate that maximum effectiveness and optimal tolerability are obtained using moderately intermittent dosing schedules.
authors.affiliation: Discovery Biology, Oncology Product Creation Unit, Eisai Inc., Andover, MA, USA.
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Towle
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nomoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Asano
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kishi
authors.forename: Melvin J
authors.initials: MJ
authors.lastname: Yu
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D005260:Female; D005663:Furans / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000008:administration & dosage* / Q000494:pharmacology; D020714:Maximum Tolerated Dose; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000401:mortality; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin; D000095662:Polyether Polyketides