Study Of Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer

This 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.

The FDA (U.S. Food and Drug Administration) has not approved Ruxolitinib for Inflammatory
Breast Cancer (IBC), but is has been approved for other uses.

Ruxolitinib is a newly discovered drug that has been shown to block a pathway (called the
IL6/JAK/Stat pathway) that may be important in cancer, including triple negative inflammatory
breast cancer. Ruxolitinib brings proteins groups together, which can result in gene (DNA)
changes. These DNA changes may stop cancer cells from growing.

Paclitaxel (also called Taxol), Doxorubicin and Cyclophosphamide (also called Adriamycin and
Cytoxan, ("AC")) are drugs FDA approved for breast cancer patients. They have been shown to
result in death of cancer cells when given as preoperative treatment of women with
inflammatory breast cancer (IBC). Laboratory studies have shown that Ruxolitinib may make
Paclitaxel more effective.

In this research study, the investigators are evaluating Ruxolitinib in combination with
Paclitaxel followed by the standard chemotherapy, AC. Researchers will also evaluate how the
IL6/JAK/Stat pathway is affected by this combination of drugs by studying biopsies and
surgical specimens.

Inclusion Criteria:

- Participants must have histologically confirmed invasive breast cancer. All histologic
subtypes are eligible.

- Patients must have known ER, PR, and HER2 status defined as triple-negative breast
cancer (TNBC), defined as:

--ER and PR <10% by immunohistochemistry, and HER2-negative ( as per ASCO/CAP
guidelines, defined as IHC 0 or 1+, or FISH ratio <2.0 or HER2 copy number <6.0).

- Patients must have the clinical diagnosis of inflammatory breast cancer as evidenced
by the onset of signs and symptoms noted below within a 6 month time-period:

- Erythema of the breast

- Edema of the skin of the breast

- Enlargement of the breast

- Age ≥ 18 years. Because no dosing or adverse event data are currently available on the
use of ruxolitinib in participants <18 years of age, children are excluded from this
study.

- ECOG performance status 0 or 1.

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

- Leukocytes ≥ 3,000/mm3

- Absolute neutrophil count ≥ 1,500/mm3

- Platelets ≥ 100,000/mm3

- Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

- AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal

- Creatinine ≤1.5 x institutional upper limit of normal OR creatinine clearance >
60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal

- Patients must be without evidence of visceral or bone involvement with metastatic
cancer on physical exam or any diagnostic study. Extensive nodal involvement is
allowed.

- Both men and women are allowed.

- The effects of ruxolitinib on the developing human fetus are unknown. For this reason
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 until
completion of chemotherapy. 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 the willingness to sign a written informed consent document.

- LVEF > 50% calculated by echocardiogram (ECHO) or MUGA

- Patients may have bilateral breast cancer so long as one breast meets criteria for
inflammatory breast cancer, and neither breast cancer has received prior therapy

Exclusion Criteria:

- Participants may not be receiving any other investigational agents.

- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- Patients with evidence of metastatic disease involvement in viscera or bone.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ruxolitinib.

- Participants receiving any medications or substances that are potent inhibitors of
CYP3A4, including grapefruit juice are ineligible. Participants receiving fluconazole
are also ineligible. (Please refer to Appendix B for the full list of potent
inhibitors and washout periods).

- Chronic corticosteroid use in excess of the equivalent of prednisone 10 mg once daily.

- Uncontrolled intercurrent illness including, but 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.

- Pregnant women are excluded from this study because paclitaxel, doxorubicin, and
cyclophosphamide have the potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk of adverse events in nursing infants secondary
to treatment of the mother with these agents, breastfeeding should be discontinued if
the mother is treated on study. These potential risks may also apply to other agents
used in this study.

- Individuals with a history of a 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 3 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 3 years: cervical cancer
in situ, and basal cell or squamous cell carcinoma of the skin.

- Known HIV-positive individuals on combination antiretroviral therapy are eligible so
long as they meet all other criteria. Known HIV-positive individuals who are not on
combination antiretroviral therapy are not eligible because these individuals are at
increased risk of lethal infections when treated with marrow-suppressive therapy.
Appropriate studies will be undertaken in participants receiving combination
antiretroviral therapy when indicated.

- Clinically significant malabsorption syndrome.

- Patients may not have received paclitaxel, doxorubicin, or cyclophosphamide as
anti-neoplastic therapy.