Romidepsin and Abraxane in Treating Patients With Metastatic Inflammatory Breast Cancer

PRIMARY OBJECTIVES:

1. To assess the safety of the combination of romidepsin plus Abraxane (paclitaxel
albumin-stabilized nanoparticle formulation) delivered weekly. (Phase I)

2. To determine the maximum tolerated dose (MTD) of romidepsin with full dose weekly
Abraxane to define a recommended phase II doses of the combination. (Phase I)

3. To assess the progression-free survival (PFS) in patients with human epidermal growth
factor receptor 2 (HER2) negative, newly diagnosed metastatic inflammatory breast cancer
treated with the combination of romidepsin and Abraxane. (Phase II)

SECONDARY OBJECTIVES:

1. To assess the safety and tolerability of the combination of romidepsin and Abraxane.

2. To determine the adverse event profile of the combination of romidepsin and Abraxane.

3. To assess the overall response rate (ORR) and clinical benefit rate (CBR) in patients
with newly recurrent inflammatory breast cancer (IBC) treated with the combination of
romidepsin and Abraxane.

OUTLINE: This is a phase I, dose-escalation study of romidepsin followed by a phase II study.

Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV)
over 30 minutes and romidepsin IV over 60 minutes 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 3 months for 2 years,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed breast carcinoma with a
clinical diagnosis of IBC based on the presence of inflammatory changes in the
involved breast, such as diffuse erythema and edema (peau d'orange), with or without
an underlying palpable mass involving the majority of the skin of the breast.
Pathological evidence of dermal lymphatic invasion should be noted but is not required
for diagnosis.

2. Patients may have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension in accordance with RECIST criteria v.
1.1 as described in detail in section 11.0 or non-measurable tumors

3. Patients must have demonstrated metastatic disease and not received >2 lines of
systemic therapy for metastatic disease

4. Age > 18 years

5. ECOG performance status 0, 1 or 2

6. Patients must have normal organ and marrow function as defined below: a) Leukocytes >
2,500/mcL b) Absolute neutrophil count > 1,500/mcL c) Hemoglobin > 9 g/dl d) Platelets
> 100,000/mcL e) Total bilirubin < 1.5 mg/dl f) AST/ALT (SGOT/SGPT) < 2.5 x ULN g)
Alkaline Phosphatase < 2.5 x ULN (unless bone metastasis is present in the absence of
liver metastasis, in which case 3.0 x ULN would be acceptable. h) Serum magnesium >
1.8 mg/dL i) Serum creatinine < 1.5 mg/dl j) Serum potassium > 3.8 mmol/L

7. Tumor negative for HER2 expression (0 or 1+ by IHC) or negative FISH testing

8. Patients must have a life expectancy of at least 12 weeks

9. Patients must be recovered from the effects of any prior surgery, radiotherapy, or
other antineoplastic therapy

10. Patients must have < Grade 2 pre-existing peripheral neuropathy per CTCAE

11. Women of childbearing potential and sexually active males must use an effective
contraception method during treatment and for three months after completing treatment

12. Negative serum or urine β-hCG pregnancy test at screening, performed no more than 72
hours prior to treatment initiation; for patients of childbearing potential

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

Exclusion Criteria:

1. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse event from agents administered
more than 4 weeks earlier

2. Patients may not be receiving any other investigational agents or active
anti-neoplastic therapies

3. Patients who have previously received romidepsin or Abraxane

4. Patients with untreated or uncontrolled brain metastases or leptomeningeal disease

5. Patients with known hypersensitivity to any of the components of romidepsin or who
have had hypersensitivity reactions to paclitaxel

6. 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

7. Any known cardiac abnormalities such as:

1. Congenital long QT syndrome

2. QTc interval ≥ 500 milliseconds

3. Myocardial infarction within 6 months of C1D1. Subjects with a history of
myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic
and have had a negative cardiac risk assessment (treadmill stress test, nuclear
medicine stress test, or stress echocardiogram) since the event may participate

4. Other significant EKG abnormalities including 2nd degree atrio-ventricular (AV)
block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50
beats/min)

5. Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see
Appendix III) In any patient in whom there is doubt, the patient should have a
stress imaging study and, if abnormal, angiography to define whether or not CAD
is present

6. An EKG recorded at screening showing evidence of cardiac ischemia (ST depression
depression of ≥2 mm, measured from isoelectric line to the ST segment). If in any
doubt, the patient should have a stress imaging study and, if abnormal,
angiography to define whether or not CAD is present

7. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class
II to IV definitions (see Appendix IV) and/or known ejection fraction <40% by
MUGA or <50% by echocardiogram and/orMRI

8. A known history of sustained ventricular tachycardia (VT), ventricular
fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently
addressed with an automatic implantable cardioverter defibrillator (AICD)

9. Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
other causes

10. Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 160/95; patients who
have a history of hypertension controlled by medication must be on a stable dose
(for at least one month) and meet all other inclusion criteria

11. Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
doses of beta-blockers)

12. Patients taking drugs leading to significant QT prolongation (See Appendix I:
Medications That May Cause QTc Prolongation)

13. Concomitant use of CYP3A4 inhibitors (see Appendix II)

8. Patients with known HIV, hepatitis B or C (However, if patients have previously been
treated for hepatitis B or C and have undetectable viral loads, they can be considered
eligible for trial)

9. Pregnant or breast feeding. Refer to section 4.4 for further detail

10. Patients with any other medical or psychological condition deemed by the investigator
to be likely to interfere with a patient's ability to sign informed consent, cooperate
and participate in the study, or interfere with the interpretation of the results