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1. Rationale and Background
Eribulin mesylate (E7389) is a structurally simplified, synthetic
analogue of the marine natural product halichondrin B. Eribulin is
a nontaxane microtubule dynamics inhibitor with potent antican-
cer effects in preclinical models of a variety of tumor types, includ-
ing breast cancer.1-4 Eribulin has a mechanism of action distinct
from other agents that target tubulin3,5-7 and, for this as well as
other reasons, may be effective in patients whose disease is resistant
to other tubulin-targeting agents. In preclinical studies, eribulin
retained activity in cell lines that were paclitaxel resistant as a result
of β-tubulin mutations.8
Following 3 phase I studies,9-11 2 phase II studies12,13 of
eribulin in extensively pretreated patients with locally advanced or
metastatic breast cancer have been completed. These trials showed
that eribulin was therapeutically active, had a manageable toler-
ability profile, and was associated with a low incidence of clini-
cally significant peripheral neuropathy. Based on these encouraging
results, 2 randomized, comparator-controlled phase III studies
were initiated in patients with locally advanced/recurrent or meta-
static breast cancer previously treated with an anthracycline and
a taxane. Study E7389-G000-305 (Study 305, the EMBRACE
study; NCT00388726) compares eribulin with the treatment
of the physician’s choice. Study E7389-G000-301 (Study 301;
Abstract
Phase III Trials of Eribulin Mesylate (E7389)
in Extensively Pretreated Patients With Locally
Recurrent or Metastatic Breast Cancer
Chris Twelves,1 Javier Cortes,2 Linda T. Vahdat,3
Jantien Wanders,4 Corina Akerele,5 Peter A. Kaufman6
Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor with a novel mechanism of action. In pre-
clinical studies, it has activity in a variety of in vivo tumor model types, including breast cancer. Following promising
results from phase I and phase II studies in patients with breast cancer, 2 open-label, randomized, controlled, parallel-
group phase III studies have been initiated, and enrollment has been completed. Both study populations comprise
patients with locally advanced/recurrent or metastatic disease pretreated with several chemotherapy regimens, in-
cluding an anthracycline and a taxane. In Study 305, eribulin is being evaluated as late-line therapy. The primary
objective is to compare overall survival (OS) between eribulin monotherapy and treatment of the physician’s choice,
and progression-free survival (PFS) is one of the secondary objectives. The 762 patients enrolled in Study 305 were
randomized in a 2:1 ratio to receive either eribulin or treatment of the physician’s choice. In Study 301, eribulin is be-
ing assessed as second-line therapy, and the primary objective is to compare eribulin and capecitabine in terms of
OS and PFS. Secondary objectives include assessments of response data, duration of response, quality of life, pain
intensity, analgesic consumption, and assessment of pharmacokinetic/pharmacodynamic relationships for eribulin.
In Study 301, the 1102 patients enrolled were randomized to receive either eribulin or capecitabine (approximately
550 patients in each arm). Tumor assessments are carried out every 8 weeks in Study 305, and every 2 cycles (each
of 3 weeks’ duration) in Study 301. Safety is also assessed in both studies.
Clinical Breast Cancer, Vol. 10, No. 2, 160-163, 2010; DOI: 10.3816/CBC.2010.n.023
Keywords: Capecitabine, EMBRACE, Microtubule dynamics inhibitor, Study design, Treatment of physician’s choice
Current Trial
Trial Numbers/Registration Dates: NCT00388726, October 13, 2006;
NCT00337103, June 13, 2006.
1Leeds Institute of Molecular Medicine, St. James University Hospital, Leeds, United
Kingdom
2Vall d’Hebron University Hospital, Barcelona, Spain
3Weill Cornell Medical College, New York, NY
4Eisai Ltd., Hatfield, Hertfordshire, United Kingdom
5Eisai Inc., Woodcliff Lake, NJ
6Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
Submitted: Jan 21, 2010; Accepted: Jan 25, 2010; Epub: Mar 5, 2010
Address for correspondence: Chris Twelves, MD, Leeds Institute of Molecular
Medicine & St. James’s Institute of Oncology, Level 4, Bexley Wing, St. James’s
University Hospital, Beckett St, Leeds, LS9 7TF, UK
Fax: 44-0-113-206-8474; e-mail: c.j.twelves@leeds.ac.uk
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA.
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160 | Clinical Breast Cancer April 2010

2. Clinical Breast Cancer April 2010 | 161
NCT00337103) compares eribulin with capecitabine. This paper
briefly describes the designs of these studies to keep clinicians
abreast of the latest developments in this rapidly changing field.
Study Objectives
Study 305
The primary objective of this study is to compare the effects of
eribulin monotherapy or treatment of the physician’s choice (as
described in the Trial Design section) on overall survival (OS) in
the patient population described above.
Secondary objectives are progression-free survival (PFS), objec-
tive tumor response rate (using Response Evaluation Criteria in
Solid Tumors [RECIST]14), duration of response, and safety.
Study 301
The primary objective is to compare the efficacy of eribulin
versus capecitabine monotherapy, in terms of OS and PFS, in the
patient population described above.
Secondary objectives are quality of life (QOL; using the
European Organization for Research and Treatment of Cancer
[EORTC] questionnaire); objective tumor response rate (RECIST);
duration of response; 1-, 2-, and 3-year survival; tumor-related pain
intensity (via a Visual Analog Scale [VAS] and analgesic consump-
tion); and safety. Eribulin population pharmacokinetic/pharmaco-
dynamic relationships are also being evaluated in this study.
Eligibility Criteria
Inclusion Criteria
Both studies included women aged ≥ 18 years with histologically
or cytologically confirmed locally advanced or metastatic breast can-
cer (Study 301) or locally recurrent or metastatic breast cancer (Study
305) previously treated with several chemotherapeutic regimens,
including an anthracycline and a taxane. In Study 305, patients must
have received 2-5 previous chemotherapy regimens (including ≥ 2
regimens for locally recurrent or metastatic breast cancer), and in
Study 301, eligible patients have received ≤ 3 previous chemothera-
peutic regimens (but no more than 2 regimens for locally advanced or
metastatic breast cancer). In both studies, patients may have received
previous treatment with trastuzumab or hormonal therapies. Other
key inclusion criteria are documented progression during or after the
last chemotherapy regimen; adequate bone marrow, liver, and renal
function; an Eastern Cooperative Oncology Group performance
status of 0-2; and a life expectancy of ≥ 3 months.
Exclusion Criteria
Key exclusion criteria common to both studies are radiation
therapy encompassing > 30% of the bone marrow, previous treat-
ment with mitomycin C or nitrosourea, pulmonary lymphangitic
involvement requiring active treatment for pulmonary dysfunc-
tion, continued anticoagulant therapy with warfarin or related
compounds (low-dose warfarin for line patency is allowed), known
brain metastases unless treated and stable, meningeal carcinomato-
sis, significant cardiovascular impairment, preexisting neuropathy
grade > 2, previous malignancy (except cervical carcinoma in situ or
nonmelanoma skin cancer) within the past 5 years, severe or uncon-
trolled intercurrent illness or infection, pregnancy or breastfeeding,
organ allografts requiring immunosuppression, positive status for
HIV, hypersensitivity to halichondrin B or its derivatives, previous
treatment with eribulin or participation in an eribulin trial, and use
of any investigational drug within 4 weeks of the start of the study.
In Study 305, patients are excluded if they have been treated with
chemotherapy, radiation, trastuzumab, or hormonal therapy in the
3 weeks before the start of the study. In Study 301, patients are
excluded if they have been treated with chemotherapy, radiation, or
biologic therapy within 2 weeks, or with hormonal therapy within
1 week of the start of the study, or if they have been previously
treated with capecitabine.
Trial Design
These are open-label, multicenter, randomized, controlled,
parallel-group phase III trials with centers in North and South
America, Europe, Australia, and South Africa for both studies,
with centers also in Asia for Study 301. Randomization is 2:1 for
eribulin versus treatment of the physician’s choice in Study 305
and 1:1 for eribulin versus capecitabine in Study 301, both with
21-day eribulin treatment cycles. Study 305 has an expected dura-
tion of approximately 2.5 years and has recruited 762 patients in
137 centers. Study 301 has an expected duration of 5.5 years and
has recruited 1102 patients in 210 centers.
Trial Design and Assessment Schedules for Studies
305 and 301a
Figure 1
aThe design represents only 1 cycle of treatment, the study termination, and the follow-up after
the patient comes off study. For Study 305, this schedule represents only eribulin administration.
bPhysical examination/vital signs and hematology/chemistry were performed at screening and
each visit during treatment; urinalysis was performed at screening, on day 1, and at the visit
before treatment cessation; a 12-lead electrocardiogram was performed at screening and at the
visit before treatment cessation (also on day 1 and day 15 for Studies 305 and 301,
respectively); a pregnancy test (if applicable) was performed at screening and on day 1; adverse
events and concomitant medications were assessed throughout the treatment period.
Abbreviation: ECOG = Eastern Cooperative Oncology Group
A
Screening
Study
305
Days
–21 to 0
Day 1 Day 8 Day 15 Every
3 Months
Within 30
Days of Final
Treatment
Treatment Follow-up
R
A
N
D
O
M
I
Z
A
T
I
O
N
B
Screening
Study
301
Days
–14 to 0
Day 15 Every
3 Months
Within 30
Days of Final
Treatment
Treatment Follow-up
R
A
N
D
O
M
I
Z
A
T
I
O
N
Day 1
Tumor Assessments
ECOG Performance Status
Safety Assessmentsb
Eribulin Administration
Capecitabine Administration (Days 1 to 14)
Day 8

3. Study 305
Patients in the eribulin arm receive eribulin mesylate 1.4 mg/m2
given as an intravenous infusion over 2-5 minutes on days 1 and 8
of each 21-day cycle (Figure 1). In the arm receiving treatment of
the physician’s choice, physicians can treat patients with any single-
agent chemotherapy, hormonal treatment, or biologic therapy
approved for the treatment of patients with cancer; radiotherapy;
or palliative treatment administered according to local practice and
defined before randomization.
In practice, a range of medications and therapies are used to treat
patients at this advanced stage of the disease, depending on the
previous treatments received, the options available at the particular
center, and the biases of individual oncologists. The arm receiving
treatment of the physician’s choice permits a direct comparison
between the effects of eribulin monotherapy and those of a vari-
ety of therapeutic and palliative options instituted by practicing
oncologists on a day-to-day basis.
For all patients, the agent chosen for the arm receiving treat-
ment of the physician’s choice is first defined and confirmed by the
investigator using an interactive voice response system. Patients are
then stratified by geographic region, HER2/neu status, and previ-
ous treatment with capecitabine, and then they are randomized to
either eribulin or treatment of the physician’s choice. This process
ensures that each agent of the physician’s choice is independently
randomized against eribulin to support subgroup analyses.
Study 301
The eribulin dose and treatment regimen is the same as in
Study 305. In the capecitabine arm, patients receive capecitabine
2.5 g/m2/day administered in 2 equal doses on days 1-14 of each
21-day cycle (Figure 1).
The study has 2 co-primary endpoints: PFS and OS. The overall
significance level of .05 will be adjusted for the multiple endpoints:
.04 will be used for testing OS, and .01 will be used for testing PFS.
The trial can be stopped early for superiority in OS but not in PFS.
Assessments
Efficacy
Tumor Assessments. Before the start of study treatment, the fol-
lowing tumor assessments are made: computed tomography (CT)
or magnetic resonance imaging (MRI) scans of the chest, abdomen,
pelvis, and any other areas of suspected disease; photographs of skin
lesions (if present); and bone scans.
In Study 305, response is assessed every 8 weeks (± 1 week),
or sooner if there is suspicion of disease progression. Scans and
photography are performed in those areas where disease was found
at baseline, and in any new areas of suspected disease. Bone scans
are only repeated during the study if clinically indicated. Tumor
responses are confirmed by a second assessment ≥ 4 weeks later.
Patients with complete/partial response or stable disease who with-
draw from treatment before disease progression continue to have
tumor assessments every 3 months until progressive disease (PD)
or the start of a new anticancer treatment.
In Study 301, the chest, abdomen, and any baseline disease areas
are scanned/photographed at screening and then between days 15
and 21 of every second cycle for the first 12 cycles, and every third
cycle subsequently starting with cycle 15. Assessments can be made
before day 15 if there is evidence of disease progression. Bone scans
are carried out every sixth cycle. If patients discontinue treatment
without PD, tumor assessments (except bone scans) are performed at
study termination (within 30 days of last study treatment) and then
every 3 months until PD or the start of another anticancer therapy.
Independent blinded review of imaging data (CT, MRI, bone
scans, x-rays, and photographs) is carried out in both studies.
Safety
Safety assessments for both studies are detailed in Figure 1.
Other Assessments
Additional assessments in Study 301 include pain intensity
(VAS), analgesic consumption, QOL (EORTC questionnaire), and
the pharmacokinetic/pharmacodynamic relationship for eribulin in
a subset of ≥ 200 patients.
Conclusion
Accrual for Study 305 occurred from November 2006 to
November 2008 in 137 centers and for Study 301 from September
2006 to September 2009 in 210 centers. Enrollment has been
completed for both studies. The need for both efficacious and
reasonably well-tolerated treatments in women with advanced or
recurrent metastatic breast cancer previously treated with an anthra-
cycline and a taxane is well recognized and reflected by this popula-
tion being actively targeted in many clinical trials. The successful,
simultaneous recruitment of such women into 2 large randomized
trials in a timely manner demonstrates the feasibility of this strategy
as part of a global development program. For further details, visit
http://www.clinicaltrials.gov, study numbers NCT00388726 and
NCT00337103.
Acknowledgments
The authors thank José Luis Traverso, MD, PhD, of Complete
Medical Communications, who provided medical writing support
funded by Eisai Corporation of North America.
Disclosures
Both studies were funded by Eisai Medical Research Inc. and Eisai
Limited.
Chris Twelves has served as an advisor to Eisai Ltd. Javier Cortes
has served as a consultant for Roche Pharmaceuticals and as an advi-
sor to Eisai Ltd. Linda T. Vahdat has received research funding from
Eisai Ltd.; Bristol-Myers Squibb; ImClone Systems Incorporated;
and Infinity Pharmaceuticals, Inc. Jantien Wanders is an employee
of Eisai Ltd. Corina Akerele is an employee of Eisai Inc. Peter A.
Kaufman has received research grant support from Eisai Ltd.
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