Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of ruxolitinib phosphate (ruxolitinib) (JAK2
inhibition) in combination with fixed dosing of pembrolizumab (anti PD-1) in patients with
advanced/metastatic triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To determine the safety profile of pembrolizumab in combination with ruxolitinib.

II. To estimate clinical tumor response in women with TNBC treated with pembrolizumab in
combination with ruxolitinib as measured by Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1.

TERTIARY OBJECTIVES:

I. To assess tumor response with immune related (ir)RECIST and associations with PDJ
amplification, PD-L1, PD-L2, JAK2 and pSTAT3 expression.

II. To determine the effect of combination targeted blockade on T- and B- cell immunity to
breast cancer tumor antigens.

OUTLINE: This is a dose-escalation study of ruxolitinib phosphate.

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and ruxolitinib
phosphate orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

After completion of study, patients are followed up every 3 or 6 months for up to 2 years.

Inclusion Criteria:

- Metastatic (stage IV) triple negative breast cancer that has progressed after at least
one prior chemotherapy regimen in the metastatic setting; non-measurable disease (i.e.
bone metastases) is permitted

- Histological confirmation of triple negative breast cancer defined as:

- Estrogen receptor =< 1% tumor staining by immunohistochemistry (IHC)

- Progesterone receptor =< 1% tumor staining by IHC

- Her2/neu by fluorescence in situ hybridization (FISH) (ratio =< 1.8) or IHC (0 or
1+)

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 x upper limit normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN or < 5 x ULN if organ involvement

- Alkaline phosphatase < 5 x ULN

- Serum creatinine =< 2 x ULN or 24 hour creatinine (Cr) clearance > 60 ml/min

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

- Ability to provide informed written consent and be able to adhere to the study visit
schedule and other protocol requirements

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Willing to provide blood samples for correlative research purposes

- Has existing archived tissue and is willing to consent to providing sample for
correlative research purposes

- Female subjects of childbearing potential should have a negative serum pregnancy =< 7
days prior to registration

- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication; subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year; Note: abstinence is acceptable if this is the
usual lifestyle and preferred contraception for the subject

- Male subjects of childbearing potential must agree to use an adequate method of
contraception starting with the first dose of study therapy through 120 days after the
last dose of study therapy; Note: abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the subject

Exclusion Criteria:

- Uncontrolled intercurrent illness including, but not limited to, active uncontrolled
infection, known positive for active infectious hepatitis, type A, B or C (past
infection allowed), or psychiatric illness/social situations that would limit
compliance with study requirements; Note: ongoing infection controlled on
antibiotics/antifungal/antiviral medications are allowed

- Any of the following prior therapies:

- Cytotoxic chemotherapy =< 14 days prior to registration

- Immunotherapy =< 14 days prior to registration

- Biologic therapy (i.e. antibody therapies) =< 28 days prior to registration

- Radiation therapy =< 14 days prior to registration

- Targeted therapies (i.e. PARP inhibitors, =< 7 days or 5 half-lives whichever is
shorter)

- Receiving any other investigational agent which would be considered as a
treatment for the primary neoplasm =< 14 days prior to registration

- Active uncontrolled central nervous system (CNS) metastases

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive

- Hypersensitivity to ruxolitinib or any of its excipients

- Major surgery =< 28 days prior to registration; Note: if subject received major
surgery, they must have recovered adequately from the toxicity and/or complications
from the intervention prior to starting therapy

- Clinically significant heart disease, including the following:

- Active severe angina pectoris prior to registration

- Acute myocardial infarction prior to registration

- New York Heart Association classification IV cardiovascular disease or
symptomatic class III disease

- Note: patients with any of the above may be allowed after discussion amongst the
investigators including the principal investigator

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to registration

- Hypersensitivity to pembrolizumab or any of its excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) =< 4 weeks prior to registration
or who has not recovered (i.e., =< grade 1 or at baseline level) from adverse events
due to agents administered more than 4 weeks earlier

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy who
has not recovered (i.e., =< grade 1 or at baseline level) from adverse events due to a
previously administered agent

- Note: subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment

- Has known history of, or any evidence of active, non-infectious pneumonitis

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

- Any of the following:

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

- Is pregnant or breastfeeding, or expecting to conceive or father children within
the projected duration of the trial, starting with the pre-screening or screening
visit through 120 days after the last dose of trial treatment

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Has received a live vaccine within 30 days of planned start of registration; Note:
seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
attenuated vaccines, and are not allowed