ACY-1215 + Nab-paclitaxel in Metastatic Breast Cancer

Breast cancer is the most common female cancer and the second most common cause of death in
women. Women with hormone receptor-negative tumors that are associated with symptomatic
visceral metastases, or hormone receptor-positive tumors that are refractory to endocrine
therapy require cytotoxic chemotherapy for disease control. The standard of care for patients
with metastatic breast cancer includes single agent taxane-based chemotherapy. Combination
chemotherapy generally provides higher rates of objective response and longer time to
progression, compared to single-agent chemotherapy. However, it is associated with increased
toxicity and is of little survival benefit. There remains an unmet need for combination
regimens incorporating new, effective and oftentimes less toxic targeted agents together with
standard chemotherapy.

Inclusion Criteria:

1. Subjects have histologically confirmed adenocarcinoma of the breast -- all breast
cancer subtypes are allowed.

2. Unresectable or metastatic breast cancer. Locally recurrent disease must not be
amenable to any local treatment with curative intent. Metastatic disease must be
demonstrated either radiographically or histologically.

3. Patients may have measurable disease only, non-measurable disease only, or both
(RECIST 1.1).

4. ECOG performance status of 0-1.

5. Must have recovered from the acute toxic effects of all prior therapy prior to
registration for this study to grade 1 or less.

6. Women and men of all races and ethnic groups are eligible for this trial.

7. Minimum number of prior treatments required given standard nab-paclitaxel dosing:

- If HER2 negative: none

- If HER2 positive: two prior regimens containing HER2 targeted therapies in the
inoperable locally advanced and/or metastatic setting. Prior therapy for
inoperable locally advanced/metastatic disease should include trastuzumab plus
pertuzumab as well as ado-trastuzumab. Pertuzumab and ado-trastuzumab must have
been previously used, unless for reasons that include, but are not limited, to
the following: intolerance to pertuzumab and/or ado-trastuzumab, medical
contraindication, regimen declined by patient, treating investigator discretion,
or medical insurance coverage issues which prevented administration of pertuzumab
or ado-trastuzumab. These reasons must be reviewed with the study chairs and
documented in the medical record and care report form. Patients who relapse
within 12 months of completing neoadjuvant/adjuvant pertuzumab or ado-trastuzumab
would be considered as having progressed on that regimen.

There is no maximum number of prior treatments allowed in the metastatic setting.

8. Age >18 years. Because breast carcinoma is a disease of adults that rarely occurs in
children, children are excluded from this study.

9. Patients must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- hemoglobin ≥9 g/dL

- total bilirubin ≤ 1.5 × the upper limit of normal

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- Serum creatinine ≤ 1.5 × the upper limit of normal or calculated creatinine
clearance ≥ 60 mL/min

10. Subject is capable of understanding the informed consent process.

11. The effects of ACY-1215 on the developing human fetus are unknown. For this reason and
because the effects of chemotherapy are known to be teratogenic, 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 she or her partner is participating in this study, she should inform her
treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 2 weeks after completion of ACY-1215 administration.

Exclusion Criteria:

1. Patients who have had chemotherapy, hormonal therapy, or radiotherapy within 2 weeks
prior to entering the study or those who have not recovered from adverse events due to
agents administered more than 2 weeks earlier. Concomitant treatment with
bone-targeted therapies such as RANKL inhibitors or bisphosphonates is allowed.

2. Patients who are receiving any other investigational agents concurrently or have
received investigational agents within 2 weeks or 5 half-lives of the compound or
active metabolites, whichever is longer before the first dose of the study treatment.

3. Patients who have received HDAC inhibitors (including valproic acid, entinostat,
vorinostat) are excluded

4. Subject is pregnant or nursing. Pregnant women are excluded from this study because
ACY-1215 is an investigational therapy with unknown potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with ACY-1215,
breastfeeding should be discontinued if the mother is treated with ACY-1215.

5. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic
brain disease who have been on a stable dose of corticosteroids for treatment of brain
metastases for at least 14 days prior to registration are eligible to participate in
the study).

6. HIV+ with a CD4 count <200 are ineligible because these patients are at increased risk
of lethal infections when treated with marrow-suppressive therapy. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated.

7. Patients receiving any medications or substances that are strong inhibitors of CYP450
3A4 isoenzyme.

8. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nab-paclitaxel.

9. 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.

10. Corrected QT interval (QTc) value > 480 msec at screening; family or personal history
of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy at
screening; previous history of drug-induced QTc prolongation or the need for treatment
with medications known or suspected of producing prolonged QTc intervals on
electrocardiogram (EKG). If QTc prolongation on screening ECG is felt to be related to
electrolyte imbalance, an EKG can be repeated after correction of electrolytes.