Cyclophosphamide and Veliparib in Treating Patients With Locally Advanced or Metastatic Breast Cancer
Cyclophosphamide and Veliparib in Treating Patients With Locally Advanced or Metastatic Breast Cancer
This phase I trial studies the side effects and best dose of cyclophosphamide and veliparib
 when given together in treating patients with breast cancer that has spread from where it
 started to nearby tissue or lymph nodes or to other places in the body. Drugs used in
 chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor
 cells, either by killing the cells, by stopping them from dividing, or by stopping them from
 spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes
 needed for cell growth. Giving cyclophosphamide together with veliparib may work better in
 treating 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)