A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies

Sanjay Goel, Alain C. Mita, Monica Mita, Eric K. Rowinsky, Quincy S. Chu, Nancy Wong, Christopher Desjardins, Fang Fang, Mendel Jansen, Dale E. Shuster, Sridhar Mani, Chris H. Takimoto

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Abstract

Purpose: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies. Experimental Design: Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosingbeg an at 0.25 mg/m2 with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized. Results: Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m2). Neutropenia was the principal DLT: At 1.4 mg/m2, two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m2. Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease. Conclusions: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m2 with further dose escalation limited by neutropenia and fatigue.

Original languageEnglish (US)
Pages (from-to)4207-4212
Number of pages6
JournalClinical Cancer Research
Volume15
Issue number12
DOIs
StatePublished - Jun 15 2009

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eribulin
Microtubules
Neutropenia
Maximum Tolerated Dose
Neoplasms
Fatigue
Pharmacokinetics
Anorexia
Tubulin
Uterine Cervical Neoplasms
Nausea
Appointments and Schedules

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. / Goel, Sanjay; Mita, Alain C.; Mita, Monica; Rowinsky, Eric K.; Chu, Quincy S.; Wong, Nancy; Desjardins, Christopher; Fang, Fang; Jansen, Mendel; Shuster, Dale E.; Mani, Sridhar; Takimoto, Chris H.

In: Clinical Cancer Research, Vol. 15, No. 12, 15.06.2009, p. 4207-4212.

Research output: Contribution to journalArticle

Goel, S, Mita, AC, Mita, M, Rowinsky, EK, Chu, QS, Wong, N, Desjardins, C, Fang, F, Jansen, M, Shuster, DE, Mani, S & Takimoto, CH 2009, 'A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies', Clinical Cancer Research, vol. 15, no. 12, pp. 4207-4212. https://doi.org/10.1158/1078-0432.CCR-08-2429
Goel, Sanjay ; Mita, Alain C. ; Mita, Monica ; Rowinsky, Eric K. ; Chu, Quincy S. ; Wong, Nancy ; Desjardins, Christopher ; Fang, Fang ; Jansen, Mendel ; Shuster, Dale E. ; Mani, Sridhar ; Takimoto, Chris H. / A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 12. pp. 4207-4212.
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abstract = "Purpose: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies. Experimental Design: Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosingbeg an at 0.25 mg/m2 with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized. Results: Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m2). Neutropenia was the principal DLT: At 1.4 mg/m2, two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m2. Fatigue (53{\%} overall, 13{\%} grade 3, no grade 4), nausea (41{\%}, all grade 1/2), and anorexia (38{\%} overall, 3{\%} grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease. Conclusions: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m2 with further dose escalation limited by neutropenia and fatigue.",
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AU - Mita, Alain C.

AU - Mita, Monica

AU - Rowinsky, Eric K.

AU - Chu, Quincy S.

AU - Wong, Nancy

AU - Desjardins, Christopher

AU - Fang, Fang

AU - Jansen, Mendel

AU - Shuster, Dale E.

AU - Mani, Sridhar

AU - Takimoto, Chris H.

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