A Randomized Phase II Study Of Eribulin Mesylate With or Without Pembrolizumab For Metastatic Hormone Receptor Positive Breast Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

In this research study, The investigators are evaluating the safety and effectiveness of
Eribulin mesylate with or without Pembrolizumab in metastatic hormone receptor positive
breast cancer.

The FDA (the U.S. Food and Drug Administration) has not approved the combination of
Pembrolizumab and Eribulin mesylate for Breast Cancer.

The FDA has not approved Pembrolizumab for this specific type of breast cancer but it has
been approved in the United States for other diseases.

The FDA has approved Eribulin mesylate as a treatment option for this type of breast cancer.

Pembrolizumab is a medicine that may treat cancer by working with the immune system. The
immune system is the body's natural defense against disease. The immune system sends types of
cells called "T cells" throughout the body to detect and fight infections and diseases,
including cancer. For some types of cancer, the T cells do not work as they should and are
prevented from attacking the tumors. Pembrolizumab is thought to work by blocking a protein
in the T cells called PD-1 ("programmed death 1"), which then may allow these cells and other
parts of the immune system to attack tumors.

Eribulin mesylate is developed from a natural substance found in a sea sponge. Eribulin
mesylate works by preventing cancer cells from multiplying.

The combination of Pembrolizumab and Eribulin mesylate is investigational. The study drugs,
when given separately, work in different ways to stop the cancer cells from growing and
spreading. However, it is not known if giving the two study drugs at the same time will have
a better anti-cancer effect than giving each treatment on its own.

Inclusion Criteria

- Patients must have histologically or cytologically confirmed Stage IV invasive breast
cancer. Patients without pathologic or cytologic confirmation of metastatic disease
should have unequivocal evidence of metastasis from physical examination or radiologic
evaluation.

- Subjects must have at least one lesion that is not within a previously radiated field
that is evaluable on computerized tomography (CT) or magnetic resonance imaging (MRI)
scan per RECIST version 1.1.46 If the subject's only evaluable disease is within a
previously radiated field, it must have demonstrated progression since the time of
radiation.

- Participants must have HR positive, HER2-negative breast cancer (ER>1% and/or, PR>1%,
HER2-negative per ASCO CAP guidelines, 2013 resulted on the primary tumor and/or a
metastatic lesion).

- Participants must have already received or been intolerant to at least two lines of
hormonal therapies (including the adjuvant or metastatic setting) or be appropriate
candidates for chemotherapy

- Prior chemotherapy: Participants are allowed to have received up to 2 prior lines of
chemotherapy in the metastatic setting. If a prior chemotherapy was given for less
than 1 cycle, it will not be counted as a prior line. The last dose of chemotherapy
must be ≥14 days prior to initiation of study therapy. Participants should be
adequately recovered from acute toxicities of prior treatment. No prior treatment with
eribulin mesylate is allowed.

- Prior biologic therapy: The last dose of biologic or investigational therapy must be
≥21 days prior to initiation of study therapy.

- Prior hormonal therapy: Hormonal therapy must have been discontinued ≥14 days prior to
initiation of study therapy. However, continuation of ovarian suppression is allowed.

- Prior radiation therapy: Participants may have received prior radiation therapy in
either the metastatic or early-stage setting. Radiation therapy must be completed ≥14
days prior to initiation of study therapy.

- Prior targeted therapy: Targeted therapy must have been discontinued ≥ 14 days prior
to initiation of study therapy.

- Biphosphonates/Denosumab: Participants on bisphosphonates/denosumab may continue
receiving bisphosphonate therapy during study treatment.

- Participants must have an archival tumor sample available (1 block or 20 unstained
slides). If no archival tissue is available, participants must be willing to undergo a
research biopsy of their disease if it is safely accessible.

- Age ≥ 18 years of age

- ECOG performance status ≤2 (Karnofsky ≥60%)

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

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- hemoglobin ≥ 8 g/dl

- total bilirubin ≤1.5 × institutional upper limit of normal (ULN)

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN (≤ 5 × institutional ULN with documented
liver metastases,

- serum creatinine ≤1.5mg/dL or calculated GFR ≥60 mL/min

- INR/PT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as long
as PT or PTT is within therapeutic range of intended use of anticoagulants

- aPTT/PTT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as long
as PT or PTT is within therapeutic range of intended use of anticoagulants

- The effects of eribulin mesylate and pembrolizumab on the developing human fetus are
unknown. Pre-clinical data was suggestive of a teratogenic effect of eribulin
mesylate. For these reasons women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) for
the duration of study participation and 4 months after the last dose of eribulin
mesylate and/or pembrolizumab. Note: abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the subject.

- Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, the treating physician and principal
investigator should be informed immediately.

- While on the study, women must not breastfeed.

- Subjects of childbearing potential are defined as those who have not been
surgically sterilized and/or have had a menstrual period in the past year

- Female subjects of childbearing potential, as defined above, must have a either a
negative urine or a negative serum pregnancy test within seven (7) days of first dose
of pembrolizumab. If a urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.

- Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria

- Chemotherapy-related or radiation-related toxicities that have not resolved to Grade 1
severity or lower, except for stable sensory neuropathy (≤ Grade 2) and alopecia.

- Participants who are receiving any other investigational agents.

- Previous treatment with eribulin mesylate or any anti-PD-1, PD-L1, or PD-L2 agent or
participation in any MK-3475 Merck studies.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to eribulin mesylate or pembrolizumab.

- Known brain metastases that are untreated, symptomatic, or require therapy to control
symptoms. Participants with previously diagnosed brain metastases are eligible if they
have completed treatment at least 4 weeks prior to registration, are neurologically
stable and absence of new neurologic symptoms for the last 4 weeks prior to study
entry, and have recovered from the effects of radiotherapy or surgery. Any
corticosteroid use for brain metastases must have been discontinued without the
subsequent appearance of symptoms for ≥2 weeks before the first study drug. Treatment
for brain metastases may have included whole brain radiotherapy, radiosurgery, or a
combination as deemed appropriate by the treating physician.

- Uncontrolled intercurrent illness, including, but not limited to uncontrolled
hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive
heart failure-New York Heart Association Class III or IV, active ischemic heart
disease, myocardial infarction within the previous six months, uncontrolled diabetes
mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months,
chronic liver or renal disease, severe malnutrition or psychiatric illness/social
situations that would limit compliance with study requirements.

- Clinically significant electrocardiogram (ECG) abnormality, including a marked
baseline prolonged QT/QTc ([QT interval/corrected QT interval], eg, a repeated
demonstration of a QTc interval >500 ms).

- Medcial condition that requires chronic systemic steroid therapy or on any other form
of immunosuppressive medication. For example, participants with autoimmune disease
that requires systemic steroids or immunosuppression agents should be excluded.
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- History or evidence of active, noninfectious pneumonitis that required treatment with
steroids.

- History of interstitial lung disease.

- Participants known to be positive for the human immunodeficiency virus (HIV),
Hepatitis B antigen (HepBsAg), or Hepatitis C virus (HCV) RNA. HIV-positive
participants on combination antiretroviral therapy are ineligible because of the
potential for pharmacokinetic interactions with Pembrolizumab and/or eribulin
mesylate. In addition, these participants are at increased risk of lethal infections.

- Individuals with a history of a second 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. Patients with other cancers diagnosed
within the past 5 years and felt to be at low risk of recurrence should be discussed
with the study sponsor to determine eligibility.

- Has received a live vaccine within 28 days of planned start of study therapy.