Phase II Study of Eribulin Mesylate, Trastuzumab, and Pertuzumab in Women With Metastatic, Unresectable Locally Advanced, or Locally Recurrent HER2-Positive Breast Cancer

All of the medications that are being tested in this study are approved by the Food and Drug
administration (FDA) for the treatment of metastatic breast cancer. However, the combination
of these three medications in participants has not yet been tested. Eribulin is a
chemotherapy agent that is approved for the treatment of metastatic breast cancer for women
who have previously received at least two prior chemotherapeutic regimens for the treatment
of their metastatic disease. Pertuzumab and trastuzumab are also both approved for the
treatment of advanced HER2-positive breast cancer. Both agents help treat breast cancer by
binding HER2 receptor. However, pertuzumab and trastuzumab bind to different parts of the
HER2 receptor. Another scientific goal of this research study is to perform gene sequencing
(gene tests) on your cancer cells (obtained from biopsies or surgery) and normal tissues
(usually blood). The results of the gene tests will be used to try to develop better ways to
treat and prevent cancers.

After the Phase I run-in, two cohorts based on prior exposure to pertuzumab were evaluated.
The target accrual for Cohort A, without prior pertuzumab, is 56 participants. Using a
two-stage design (n=34 stage 1, n=22 stage 2), there is 90% power assuming 10% Type I error
to determine whether objective response (OR) rate is consistent with the alternative rate of
40% versus the null rate of 24%. There is 57% probability of stopping the trial at stage one
if the true OR rate is 24%. Cohort B, with prior pertuzumab, is evaluated using a single
stage design. There is 91% power to detect an improvement in OR from 10% to 30% with accrual
of 25 participants.

Inclusion Criteria:

Participants must meet the following criteria on screening examination to be eligible to
participate in the study:

- Participants must have invasive primary tumor or metastatic tissue confirmation of human
epidermal growth factor receptor 2 (HER2)-positive status, defined as presence of one or
more of the following criteria: Over-expression by immunohistochemistry (IHC) with score of
3+ AND/OR HER2 gene amplification (> 6 HER2 gene copies per nucleus or a FISH ratio [HER2
gene copies to chromosome 17 signals] of ≥ 2.0) Note: Participants with a negative or
equivocal overall result (FISH ratio of <2.0 or ≤ 6.0 HER2 gene copies per nucleus) and IHC
staining scores of 0, 1+, 2+ are not eligible for enrollment.

- Participants must have metastatic, unresectable locally advanced, or locally recurrent
HER2-positive breast cancer. For the phase II portion of the study, it is required
that participants have measurable disease, as defined by RECIST 1.1, which can be
accurately evaluated on computerized tomography (CT) or magnetic resonance (MRI).
Measurable disease is defined as: at least one lesion of >10 mm in the longest
diameter for a non-lymph node or >15 mm in the short-axis diameter for a lymph node
which is serially measurable according to RECIST 1.1.criteria.1

- Participants must have received at least 1 line of chemotherapy for advanced or
metastatic breast cancer and/or relapse/progressed while on or within 6 months of
completion of neoadjuvant or adjuvant trastuzumab. Prior pertuzumab is allowed in the
phase II portion of the trial.

- Participants must have had prior trastuzumab therapy (either in the adjuvant or
metastatic setting).

- Participants must be at least 2 weeks out from prior endocrine therapy,
chemotherapy,radiotherapy, or other cancer-directed therapy (including novel agents),
with adequate recovery of toxicity to baseline, or grade ≤1, with the exception of
alopecia and hot flashes. Participants may have initiated bisphosphonate/denosumab
therapy prior to start of protocol therapy. Biphosphonate/denosumab therapy may
continue during protocol treatment. Such participants will have bone lesions
considered evaluable for progression. Washout for trastuzumab is not necessary.

- Women and men, age 18 years at the time of informed consent.

- Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status
0-1 or a Karnofsky Performance Scale (KP) 70%.

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count > 1,500/mcL

- Platelets > 75,000/mcL

- Hemoglobin >9g/dl

- Total bilirubin ≤2.0 X institutional upper limit of normal

- Aspartate Aminotransferase (AST, SGOT)/ALT(Alanine Aminotransferase, SGPT) ≤ 3 X
institutional ULN without liver metastases, or ≤ 5 times institutional upper limit
normal (ULN) with liver metastases (if liver metastases felt to be cause of Liver
function tests (LFT) abnormalities)

- Alkaline phosphatase (ALP) ≤3 x institutional upper limit of normal If total ALP is
>3x institutional upper limit normal (in the absence of liver metastasis) or >5x
institutional upper limit of normal (in subjects with liver metastasis) AND the
subject is known to have bone metastases, then liver ALP isoenzyme should be used to
assess liver function rather than total ALP.

- Creatinine 2.0 mg/dL or creatinine clearance ≥50 mL/min.

- left ventricular ejection fraction (LVEF) ≥50%, as determined by
radionucleoventilugrams (RVG) (multi-gated acquisition-MUGA) or Echocardiogram (ECHO)
within 60 days prior to initiation of protocol therapy.

- Adequate IV access

- The effects of eribulin mesylate, trastuzumab, and pertuzumab on the developing human
fetus are unknown. Pre-clinical data was suggestive of a teratogenic effect of
eribulin mesylate. Pertuzumab caused oligohydramnios, delayed renal development and
embryo-fetal deaths in pregnant cynomolgus monkeys. In the post-marketing setting,
cases of oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus
have been reported in pregnant women receiving trastuzumab. For these reasons women of
child bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

- Ability to understand and willingness to sign a written informed consent document
(approved by Institutional review board or independent ethics committee) obtained
prior to any study procedure, with the understanding that the subject may withdraw at
any time without prejudice.

- Laboratory tests required for eligibility must be completed within 14 days prior study
entry. Baseline tumor measurements must be documented from tests within 28 days of
study entry. Other non-laboratory tests must be performed within 28 days of study
entry.

- For the Phase 2 portion of the study; patients must have tissue that is amenable to
biopsy and must be willing to undergo research biopsy.

Exclusion Criteria: - Participants who exhibit any of the following conditions at screening
will not be eligible for admission into the study:

- Participants receiving any other study agents.

- Participants receiving any other cancer directed concurrent therapy; such as
concurrent chemotherapy, radiotherapy, or hormonal therapy. Concurrent treatment with
biphosphonates/denosumab is allowed but should be started before starting treatment on
study.

- Active brain metastases: Participants with previously diagnosed brain metastases are
eligible if they have completed treatment at least one month prior to enrollment, are
neurologically stable, and have recovery from effects of radiotherapy or surgery.

- History of allergic reaction attributed to compounds of similar chemical or biologic
composition to eribulin mesylate, trastuzumab or pertuzumab, which cannot be managed
by premedication.

- Participants who previously received eribulin mesylate are not eligible for enrollment
on the phase II portion.

- Prior chemotherapy, targeted therapy, hormonal therapy, or radiation therapy
(including any investigational agents) within 2 weeks prior entering the study or
those who have not recovered adequately from adverse events (AEs) due to agents
administered more than 4 weeks earlier (excluding alopecia and hot flashes). A washout
period is not necessary for trastuzumab (or pertuzumab for run-in patients when
applicable).

- A baseline corrected QT interval of > 470 ms.

- Pre-existing neuropathy ≥ grade 2 (NCI Common Toxicity Criteria for Adverse Events
(CTCAE) Version 4.0)

- Uncontrolled intercurrent illness including, not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements or other significant diseases or disorders that, in the
investigator's opinion, would exclude the subject from participating in the study

- Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs,
resulting in grade 2 or higher dyspnea at rest.

- Currently pregnant or breast-feeding. All females must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of β-Human Chorionic
Gonadotropin (β-Hcg) at the Baseline visit [within 7 days of the first dose of study
treatment]). Females of childbearing potential must agree to use a medically
acceptable method of contraception (e.g., abstinence, an intrauterine device, a
double-barrier method such as condom + spermicidal or condom + diaphragm with
spermicidal, a contraceptive implant, an oral contraceptive or have a vasectomized
partner with confirmed azoospermia) throughout the entire study period and for 30 days
after discontinuation of study treatment. The only subjects who will be exempt from
this requirement are postmenopausal women (defined as women who have been amenorrheic
for at least 12 consecutive months, in the appropriate age group, without other known
or suspected primary cause) or subjects who have been sterilized surgically or who are
otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month
before start of study treatment, hysterectomy, or bilateral oophorectomy with surgery
at least 1 month before start of study treatment). Current, ongoing protocols
containing pertuzumab have included continuous pregnancy monitoring during the trial
and for six months after the last dose of study drug is administered. Because of the
long half-life of pertuzumab, women should be warned not to become pregnant for at
least six months after completion of treatment.

- Individuals with a history of different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 5 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer
in situ, and non-melanoma cancer of the skin.