Dinaciclib and Epirubicin Hydrochloride in Treating Patients With Metastatic Triple-Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of dinaciclib given in combination with
epirubicin in patients with metastatic triple negative breast cancer.

SECONDARY OBJECTIVES:

I. To determine the predictive value of myeloid cell leukemia sequence 1 protein (MCL-1), low
molecular weight cyclin E (LMW-E), and tumor grade as predictors of biologic response (i.e.
induction of apoptosis) in tumors treated with therapy.

II. To evaluate the efficacy of combination therapy. III. To determine the effects of therapy
on proliferation as measured by proliferation-related Ki-67 antigen (Ki67) and apoptosis as
measured by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling assay
(TUNEL).

OUTLINE: This is a dose-escalation study of dinaciclib.

Patients receive dinaciclib intravenously (IV) over 2 hours on day 1 and epirubicin
hydrochloride IV over 30 minutes on day 2. Treatment repeats every 21 days for up to 12
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must have histologically confirmed estrogen receptor (ER)/progesterone
receptor (PR)/human epidermal growth factor receptor 2 (HER2) negative carcinoma of
the breast that is metastatic or unresectable and for which standard curative or
palliative measures do not exist or are no longer effective; for purposes of this
study, triple negative disease will be tumors that have ER/PR < 10% and HER2 =< 1+ by
immunohistochemistry (IHC) or HER2 fluorescent in situ hybridization (FISH)
non-amplified (ratio < 2)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Patients must have no more than two prior chemotherapy regimens for metastatic breast
cancer; in patients who develop disease recurrence within 6 months of adjuvant or
neoadjuvant chemotherapy, the adjuvant or neoadjuvant therapy will be considered one
prior regimen for metastatic disease

- Life expectancy of greater than 3 months

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal limits unless clinical diagnosis of Gilbert's syndrome

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Patients must be disease free of prior malignancy for >= 5 years with the exception of
curatively treated squamous cell carcinomas of the skin or carcinoma in situ of the
cervix or breast

- Must have at least one site of objective measurable or evaluable disease; baseline
measurements and evaluations must be obtained within 4 weeks of start of therapy

- Patients must have no history of prior therapy with dinaciclib

- Concurrent use of hormonal therapy is not permitted; concurrent radiation therapy is
not permitted; bisphosphonates are allowed, provided that they were started no less
than two weeks prior to initiating protocol therapy

- Patients must have completed and recovered from the effects of prior chemotherapy (<
grade 2 toxicity) excluding alopecia

- Women of child-bearing potential and men must agree to use adequate contraception
(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 4 months after completion of dinaciclib administration

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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events

- Patients who are receiving any other investigational agents

- Patients with untreated brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition as epirubicin or dinaciclib

- Patients receiving any medications or substances that are inhibitors or inducers of
cytochrome P450 family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) are ineligible

- 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; breastfeeding should be discontinued if
the mother is treated with dinaciclib

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients who have had prior organ allograft or require immunosuppressive therapy

- Patients who have received a cumulative dose of doxorubicin of greater than 360 mg/m^2
or epirubicin of greater than 600 mg/m^2; patients who have received > 240 mg/m^2 of
doxorubicin or > 400 mg/m^2 of epirubicin should be advised to undergo evaluation of
left ventricular ejection fraction (LVEF) with echocardiogram or multi gated
acquisition scan (MUGA) prior to initiating therapy

- Patients with a history of New York Heart Association class 3 or 4 heart failure, or
history of myocardial infarction, unstable angina or cerebral vascular accident (CVA)
within 6 months of protocol registration

- LVEF < 50% by MUGA or echocardiogram (ECHO)

- Patients who have history of PR prolongation or atrioventricular (AV) block