Cyclophosphamide and Veliparib in Treating Patients With Locally Advanced or Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of veliparib (ABT-888) that can be combined
with metronomic dose cyclophosphamide in patients with metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether the macroH2A1.1 and poly (adenosine diphosphate [ADP]-ribose)
polymerase 1 (PARP1) expression status in archival paraffin embedded tumor specimens from
either the primary tumor or metastatic disease is predictive of clinical benefit with
veliparib (ABT-888) plus cyclophosphamide.

OUTLINE: This is a dose-escalation study.

Patients receive veliparib orally (PO) once daily (QD) and cyclophosphamide PO QD on days
1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Phase I: Patients must have histologically confirmed breast cancer (metastatic breast
cancer [MBC]) that is human epidermal growth factor receptor 2 (HER2/neu) negative (as
determined by local pathology or reference laboratory), and have disease that is
metastatic (stage IV [TxNxM1]) or locally advanced and not amenable to potentially
curative surgical resection (eg, clinical stage IIIB-C)

- HER2/neu negative disease (performed on primary tumor and/or metastatic lesion using
commercially available/approved assay in local institutional or reference laboratory),
according to American Society of Clinical Oncology (ASCO)/College of American
Pathologists (CAP) guidelines

- National Comprehensive Cancer Network (NCCN) guidelines recommend for metastatic
breast cancer "…biopsy documentation of first recurrence, if possible, and
determination of hormone receptor status (estrogen receptor [ER] and progesterone
receptor [PR]) and HER2 status…."; therefore, histologic and/or cytologic confirmation
of metastatic disease is encouraged whenever feasible, but not required; in some
circumstances, histologic confirmation may not be feasible (eg, bone metastases not
amenable to biopsy and elevated cancer antigen [CA]27-29 tumor marker); for patients
who have had histologic confirmation of metastatic disease, it is required that the
biopsy confirm that the metastatic tumor is ER and/or PR positive, and HER2/neu
negative; for patients in whom biopsy confirmation of metastatic disease is not
feasible, it is required that the primary tumor be ER and/or PR-positive and HER2/neu
negative

- Measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) or
non-measurable disease, with measurement obtained within 4 weeks of registration

- Phase I: Patients must have received at least one prior chemotherapy regimen for
metastatic disease; patients with deleterious germ line mutations in breast cancer
(BRCA)1 or BRCA2 are not required to have received prior chemotherapy for metastatic
disease

- Patients must have had progressive disease after at least one line of endocrine
therapy for metastatic disease (includes relapse while receiving endocrine therapy);
there should be at least 1 week interval between the last endocrine treatment for an
aromatase inhibitor and at least 2 weeks for tamoxifen or fulvestrant

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Karnofsky >=
60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dl (per manufacturer recommendation)

- Total bilirubin within normal institutional limits (unless isolated indirect
hyperbilirubinemia due to Gilbert's disease)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 × 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 with a history of brain metastases are eligible if they have been treated
with radiation and have stable brain metastases at least 3 months after radiation and
must also be off steroids

- Patients must be able to swallow whole capsules and tolerate oral medications

- 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; being not of childbearing potential is defined
as: (1) prior hysterectomy, or (2) no menstrual period for at least 24 months; 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

Exclusion Criteria:

- Patients who have radiotherapy within 3 weeks prior to entering the study or those who
have not recovered from adverse events due to systemic agents administered more than 3
weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases with active symptoms or requiring anticonvulsive
medications, or steroids should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to veliparib (ABT-888) or cyclophosphamide used in the study

- Evidence of complete or partial bowel obstruction or other unable to take oral
medications

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption

- Patients unable to swallow whole capsules

- 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 (positive pregnancy test) or lactating women will be excluded from the study;
also, unwillingness to use effective means of contraception in subjects with
child-bearing potential will be excluded from the study; women of child-bearing
potential must use two forms of contraception (i.e., barrier contraception and one
other method of contraception) at least 4 weeks prior to study entry, for the duration
of study participation

- Patients with active severe infection; known infection with human immunodeficiency
virus (HIV), hepatitis B virus, hepatitis C virus, or severe concurrent illness will
be excluded from the study; HIV-positive patients on combination antiretroviral
therapy are ineligible

- Patients with a history of seizure disorder requiring antiepileptics who have had a
seizure episode within the last 6 months

- Prior treatment with veliparib (ABT-888) or other PARP inhibitors (e.g., olaparib)