Eribulin Mesylate or Paclitaxel as First- or Second-Line Therapy in Treating Patients With Recurrent Stage IIIC-IV Breast Cancer

PRIMARY OBJECTIVES:

I. To demonstrate that patient-reported Patient-Report Outcomes Version of the Common
Terminology Criteria for Adverse Events (PRO-CTCAE) data will be able to detect differences
in symptoms between participants treated witheribulin mesylate (eribulin) and standard weekly
paclitaxel at 12 weeks.

II. To validate rs7349683 in EPHA5 as a predictor of peripheral neuropathy from treatment
with a microtubule targeting agent (i.e., eribulin or paclitaxel).

SECONDARY OBJECTIVES:

I. To compare overall survival, progression free survival (PFS), objective response rate
(ORR), duration of response (DOR), and time to treatment failure (TTF) in patients receiving
eribulin versus standard weekly paclitaxel.

II. To compare the 12 month rate of disease progression in patients receiving eribulin versus
standard weekly paclitaxel.

III. To evaluate the clinical value and feasibility of collecting patient-reported symptom
toxicity information via the Patient-Report Outcomes Version of the Common Terminology
Criteria for Adverse Events (PRO-CTCAE).

IV. To further validate the PRO-CTCAE sensory neuropathy items. V. To compare patient
reported neurotoxicity between arms using the European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Chemotherapy-Induced Peripheral
Neuropathy 20 (CIPN20) instrument.

VI. To assess the toxicities in patients receiving eribulin versus standard weekly
paclitaxel.

CORRELATIVE OBJECTIVES:

I. To compare new metastasis free survival in patients receiving eribulin versus standard
weekly paclitaxel.

II. To explore the relationship between common single nucleotide polymorphisms in FGD4, FZD3,
and VAC14 as predictors of peripheral neuropathy from treatment with a microtubule targeting
agent (i.e., eribulin or paclitaxel).

III. To evaluate circulating nucleosomes and the apoptosis associated M30 neo-epitope as
potential biomarkers associated with clinical benefit from treatment with eribulin
specifically or the microtubule dynamics inhibitors in general.

VI. To evaluate tubulin isotype expression, mutations, and signaling pathway modifications in
tumor tissue as potential biomarkers associated with clinical benefit from treatment with
eribulin specifically or the microtubule dynamics inhibitors in general.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive eribulin mesylate intravenously (IV) over 2-5 minutes on days 1 and
8. Courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.

ARM B: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks.

Inclusion Criteria:

- Informed consent document signed and dated by patient

- Histologic confirmation of invasive adenocarcinoma originating in the breast

- Stage IV disease or stage IIIC disease (using the 7th edition American Joint Committee
on Cancer [AJCC] criteria) not amenable to local therapy

- Clinical or radiographic evidence of disease progression

- Documentation of HER2 negative breast cancer at the time of protocol registration;
(Note: HER2 negativity is defined as 0 or 1+ by immunohistochemistry OR nonamplified
or equivocal by fluorescence in situ hybridization [FISH]; status may be defined on
the basis of historic results on the breast primary or a metastatic site, whichever is
most recent; repeat biopsies are not required for participation in this protocol)

- Known hormone receptor status at the time of protocol registration; (Note: estrogen
receptor [ER] and/or progesterone receptor [PgR] status are considered positive with a
cut-off of >= 1% invasive tumor cells; status may be defined on the basis of historic
results on the breast primary or a metastatic site, whichever is most recent; repeat
biopsies are not required for participation in this protocol)

- Patients must demonstrate resolution of all toxicities related to prior chemotherapy,
endocrine therapy, targeted therapy, or biologic therapy to grade =< 1, including
peripheral neuropathy, with the exception of alopecia (any grade permissible)

- No more than one prior chemotherapy regimen for advanced or metastatic breast cancer
is allowed; prior chemotherapy for metastatic disease must have been completed >= 14
days prior to randomization

- Any single agent therapy, and any combination of cytotoxic, endocrine, biological
targeted agents, and/or humanized antibodies, scheduled to be administered as a
preplanned treatment, given concomitantly, sequentially or both, is considered
one regimen

- Planned neoadjuvant chemotherapy and postoperative adjuvant chemotherapy is
considered one regimen

- If the dosing of one or more of the chemotherapy components of a regimen must be
reduced for toxicity, the modified version of the original regimen is not
considered a new regimen

- If one or more of the chemotherapy components of a regimen must be omitted for
toxicity, the modified version of the original regimen is not considered a new
regimen

- If one of the chemotherapy components of a regimen must be replaced with another
similar drug of the same therapeutic class, the modified version of the original
regimen is not considered a new regimen; however, if a new component, dissimilar
to any of the original components, is added to the regimen, the modified version
is considered a new regimen

- If chemotherapy is interrupted for surgery or radiotherapy and then continues
with an unchanged schedule and components, treatment is considered as one regimen
despite the interruption

- Prior treatment may include a taxane as per the following criteria:

- Prior taxane (including paclitaxel) in the adjuvant or neoadjuvant setting is
allowed, provided that the interval between the completion of (neo)adjuvant
therapy and disease recurrence is > 12 months

- Prior taxane in the metastatic setting is allowed, provided that the agent
administered in the metastatic setting was not standard paclitaxel

- Any number of prior endocrine therapies is allowed and must be discontinued prior to
randomization

- Any number of biologic therapies (e.g., bevacizumab) or immunotherapies is allowed in
the absence of co-administered chemotherapy and must have been completed >= 28 days
prior to randomization

- Prior treatment with an investigational agent is allowed but must have been completed
>= 28 days prior to randomization with resolution of all treatment-related toxicities
to grade =< 1.

- Minor surgical procedures must be completed >= 7 days prior to randomization with
documentation of adequate recovery from associated complications to grade =< 1; these
include (but are not limited to) laparoscopy, thoracoscopy, bronchoscopy,
mediastinoscopy, endoscopic ultrasonography, skin biopsy, percutaneous needle biopsy,
and routine dental procedures; as a precautionary measure, it is recommended, but not
strictly required, that placement of a central venous access device, thoracentesis, or
paracentesis be done 7 days before the initiation of protocol directed chemotherapy
with documentation of adequate recovery from associated complications to grade =< 1

- Major surgical procedures and open biopsies must be completed >= 28 days prior to
randomization with documentation of adequate recovery from associated complications to
grade =< 1

- Prior radiotherapy must be completed >= 14 days prior to randomization with
documentation of adequate recovery from associated toxicities to grade =< 1

- Treatment with bisphosphonates or denosumab is allowed and recommended per the
standard of care

- Therapeutic anticoagulation is allowed for patients on a stable dose of warfarin or
low molecular weight heparin

- Measurable disease is defined as at least one lesion that can be accurately measured
with the longest diameter as >= 1.0 cm by computed tomography (CT) scan or >= 1.0 cm
with calipers by clinical examination; the exceptions to these criteria are pathologic
lymph nodes, which must be >= 1.5 cm in the short axis when assessed by CT scans with
slice thickness =< 0.5 cm

- Non-measurable lesions include the following: small lesions (longest diameter < 1.0 cm
for all lesions other than pathologic lymph nodes, which are >= 1.0 cm and < 1.5 cm in
the short axis), bone metastases, pleural effusions, pericardial effusions, ascites,
inflammatory breast disease, leptomeningeal disease, lymphangitis pulmonis,
lymphangitis cutis, and abdominal masses not followed by CT or magnetic resonance
imaging (MRI)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

- Life expectancy of > 12 weeks

- Patients with a history of resected brain metastases are eligible only if they are
asymptomatic and have stable MRI scans for 3 consecutive months, including =< 28 days
of study registration

- Patients who receive stereotactic radiosurgery or whole brain radiation for brain
metastases are eligible only if they are asymptomatic and have stable MRI scans for 3
consecutive months, including =< 28 days of study registration

- Obtained =< 7 days prior to registration: Absolute neutrophil count >= 1500/uL

- Obtained =< 7 days prior to registration: Platelet count >= 100,000/uL

- Obtained =< 7 days prior to registration: Hemoglobin >= 9 g/dL

- Obtained =< 7 days prior to registration: Total bilirubin =< 1.5 times the upper limit
of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert?s syndrome

- Obtained =< 7 days prior to registration: Serum glutamic-oxaloacetic transaminase
(SGOT) (aspartate aminotransferases [AST]) and serum glutamate pyruvate transaminase
(SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN except in the case of liver
metastases, where =< 5 x ULN is allowed

- Obtained =< 7 days prior to registration: Creatinine =< 2.0 mg/dL or creatinine
clearance > 50 mL/min

- Obtained =< 7 days prior to registration: Corrected QT (QTc) interval =< 500 msec on
the baseline electrocardiogram

- Negative pregnancy test done =< 72 hours prior to registration for women of
childbearing potential only; Note: all female subjects will be considered to be of
child-bearing potential unless they are postmenopausal (at least 12 months consecutive
amenorrhea, in the appropriate age group and without other known or suspected cause),
or have been sterilized surgically (i.e., bilateral tubal ligation >= 1 menstrual
cycle prior to randomization, or have undergone a hysterectomy and/or bilateral
oophorectomy)

- Female subjects of child-bearing potential must agree to use highly effective
contraception during the study treatment and for 3 months after the final dose of
study treatment; female subjects exempt from this requirement are subjects who
practice total abstinence; if currently abstinent, the subject must agree to use
a double barrier method of contraception (i.e., condom and occlusive cap
[diaphragm or cervical/vault caps]) with spermicide or until they are established
on highly effective contraception for at least one menstrual cycle if they become
sexually active during the study treatment and for 3 months after the final dose
of study treatment

- Highly effective contraception includes:

- Placement of intrauterine device or system

- Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault cap) with spermicide

- Vasectomized partner with confirmed azoospermia

- Male subjects and their female partner who are of child-bearing potential (as
defined above), and are not practicing total abstinence, must agree to use highly
effective contraception during study treatment and for 3 months after the final
dose of study treatment; if currently abstinent, the subject must agree to use a
double barrier method of contraception if they become sexually active, or until
they are established on highly effective contraception as described above

- Ability to complete questionnaire(s) independently or with assistance

- Willingness to provide blood and tissue samples for correlative research purposes;
(Note: these tissue samples are from archived tissue, if available; new biopsies are
not required)

- Ability to comprehend and respond to questions using a telephone keypad

Exclusion Criteria:

- Prior malignancy, other than carcinoma in situ of the cervix and non-melanoma skin
cancers, unless the prior malignancy was diagnosed and definitively treated >= 5 years
previously, there is no subsequent evidence of recurrence, and the patient is
considered by a physician to be at < 30% risk of relapse

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Presence of a serious nonhealing wound, ulcer, or bone fracture

- History of Common Terminology Criteria for Adverse Events (CTCAE) grade >= 3
hypersensitivity to paclitaxel or Cremophor EL

- Pre-existing peripheral neuropathy grade ?= 2 at registration

- Significant cardiovascular impairment (e.g., New York Heart Association congestive
heart failure of grade II or above, unstable angina, myocardial infarction within the
past 6 months, or serious cardiac arrhythmia)

- Subjects with known positive human immunodeficiency virus (HIV) status

- History of stroke or transient ischemic attack =< 6 months prior to registration

- History of uncontrolled seizures; (Note: patients are eligible for the study if the
seizures are well controlled with standard medications)

- Severe or uncontrolled intercurrent illness/infection

- Concurrent administration of any other investigational agent considered to have
potential efficacy in the treatment of breast cancer

- Prior exposure to eribulin mesylate