PRIMARY OBJECTIVES:
I. To evaluate the feasibility of using talazoparib prior to initiating standard neoadjuvant
therapies.
II. To evaluate the toxicity profile in women taking talazoparib in the neoadjuvant setting.
SECONDARY OBJECTIVES:
I. To provide first estimate of clinical response to talazoparib in the neoadjuvant setting
in a pilot trial setting.
II. To evaluate biomarkers of therapy efficacy as well as initiate patient derived xenograft
(PDX) models: targeted or whole exome sequencing for BRCA pathway mutations and other somatic
and germline alterations; ribonucleic acid (RNA) sequencing; evaluation of changes in immune
response; transcriptional profile to assess triple negative breast cancer (TNBC) subtype,
BRCA-ness signature and putative PARP sensitivity predictors; functional proteomics with
reverse phase protein array (RPPA); generate PDX models and mammosphere cultures from patient
derived tumors; PTEN, gamma-H2A histone family, member x (gamma-H2A.X), Ki-67 and cleaved
caspase 3 by immunohistochemistry (IHC).
OUTLINE:
Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Treatment repeats
every 28 days for up to 6 cycles in the absence of disease progression or unacceptable
toxicity. Patients then proceed to the standard of care therapy of the treating physician's
choice.
After completion of study treatment, patients are followed up until the day after definitive
breast surgery.
Inclusion Criteria:
- Signed written informed consent
- Histologically confirmed primary invasive adenocarcinoma of the breast with the size
of the primary tumor being at least 1 cm on imaging by either mammography, ultrasound
or breast magnetic resonance imaging (MRI)
- Negative human epidermal growth factor receptor 2 (HER-2)/neu- disease defined as
patients with fluorescence in situ hybridization (FISH) ratio < 2.0 or < 6.0 HER2 gene
copies per nucleus, and IHC staining scores of 0, 1+, or 2+
- No treatment for current primary invasive adenocarcinoma of the breast such as
irradiation, chemotherapy, immunotherapy, investigational therapy or surgery; previous
treatment for breast and/or ovarian cancer with chemotherapy, endocrine therapy,
surgery and radiation are allowed if >= 3 years prior to current diagnosis and there
is no clinical evidence of metastatic disease
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Baseline multi gated acquisition scan (MUGA) or echocardiogram scans with left
ventricular ejection fraction (LVEF) of > 50%
- Absolute neutrophil count (ANC) >= 1,500/uL
- Platelets >= 100,000/uL
- Hemoglobin (Hgb) >= 9 g/dL
- Creatinine clearance > 50 ml/min
- Total bilirubin =< 1.5 X upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN
- Negative serum or urine pregnancy test for women within 7 days of receiving the first
dose of the study medication for women of childbearing potential; women will be
considered not of childbearing potential and exempt from pregnancy testing if they are
either a) older than 50 and amenorrheic for at least 12 consecutive months following
cessation of all exogenous hormonal treatments, or b) have documentation of
irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or
bilateral salpingectomy, but not tubal ligation
- Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the
last dose of investigational product; men on study also must be using contraception
- Identified deleterious mutation in BRCA 1 or 2 genes (this does not include variants
of uncertain significance)
- Eligible to receive standard of care chemotherapy and/or surgery based upon standard
practices or institutional guidelines
Exclusion Criteria:
- Women who are pregnant (including positive pregnancy test at enrollment or prior to
study drug administration) or breast-feeding
- Disease free of prior malignancy for < 3 years with the exception of curatively
treated basal carcinoma of the skin or carcinoma in situ of the cervix
- Any other previous antitumor therapies for the current cancer event
- Has had major surgery within 21 days before cycle 1 day 1
- Gastrointestinal tract disease or defect with associated malabsorption syndrome
- Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
- Myocardial infarction within 6 months before starting therapy, symptomatic congestive
heart failure (New York Heart Association > class II), unstable angina, or unstable
cardiac arrhythmia requiring medication
- Serious intercurrent infections or non-malignant medical illness that are uncontrolled
or the control of which may be jeopardized by this therapy
- Psychiatric disorders or other conditions rendering the subject incapable of complying
with the requirements of the protocols
- Unable to take oral medications
- Known to be human immunodeficiency virus positive
- Known active hepatitis C virus, or known active hepatitis B virus
- Concurrent disease or condition that would interfere with study participation or
safety, such as any of the following:
- Active, clinically significant infection either grade > 2 by National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version
(v)4.03 or requiring the use of parenteral anti-microbial agents within 14 days
before day 1 of study drug
- Clinically significant bleeding diathesis or coagulopathy, including known
platelet function disorders
- Non-healing wound, ulcer, or bone fracture
- Known hypersensitivity to any of the components of talazoparib
