This is an open-label, two-stage, multi-arm Phase 1 study designed to evaluate the safety and
preliminary efficacy of combining niraparib with four standard chemotherapy regimens used to
Niraparib is an oral, selective poly ADP ribose polymerase (PARP)-1 and PARP-2 inhibitor. A
strategy of combining a PARP inhibitor, as a chemopotentiator, with chemotherapy is a
promising approach in the treatment of triple-negative breast cancer. This study will
evaluate the combination of niraparib with several standard chemotherapy regimens used to
treat breast cancer to determine a recommended Stage 2 dose (RS2D) of chemotherapy regimens
with niraparib. Stage 1 will be conducted in subjects with metastatic TNBC and will include 4
chemotherapy treatment arms in escalating dose levels (Arm 1: doxorubicin + cyclophosphamide
(AC) every 14 days with pegfilgrastim (or biosimilar) for 4 cycles followed by AC every 21
days; Arm 2: AC every 21 days; Arm 3: weekly paclitaxel; Arm 4: weekly paclitaxel +
carboplatin every 21 days), each combined with oral daily niraparib. Treatment will continue
until disease progression, unacceptable toxicity, or subject withdrawal.Stage 2 will be
conducted in subjects with non-metastatic TNBC. Subjects will receive neoadjuvant
chemotherapy with either AC every 14 days (Arm 1A) or every 21 days (Arm 2A) at the RS2D of
chemotherapy combined with oral daily niraparib from Stage 1. Treatment will continue for 4
Subject must meet all of the following applicable inclusion criteria to participate in this
1. Able to understand and willing to provide written informed consent and HIPAA
authorization for release of personal health information. NOTE: HIPAA authorization
may be included in the informed consent or obtained separately.
2. Male or female and age ≥ 18 years at the time of consent.
3. ECOG Performance Status of 0, 1 or 2 (Stage 1), or 0-1 (Stage 2) within 14 days prior
to day 1 of treatment.
4. Histologically or cytologically confirmed hormone receptor negative tumor (estrogen
and progesterone) on pathology immunohistochemistry (IHC) assessment defined as <10%
staining and HER2-negative, non-overexpressing defined by an IHC 0 or 1+ or
fluorescence in-situ hybridization (FISH) HER2:CEP17 ratio < 2.0 with an average HER2
gene copy number of <4 signals/nucleus, and:
Stage 1 (metastatic):
a. Measurable (by RECIST v1.1) or evaluable lesions
Stage 2 (non-metastatic, treatment naïve, with no prior excisional
1. Primary tumor size ≥ 2 cm by at least one radiographic or clinical measurement.
NOTE: this requirement does not apply to subjects with inflammatory TNBC.
2. Clinical stage at presentation: cT1c-cT4, cN0-cN3
5. Tumor tissue:
Willing to provide tumor tissue for research purposes. Fresh biopsy of metastatic
lesion prior to day 1 of treatment preferred if feasible. If fresh biopsy of
metastatic lesion is not feasible, fresh biopsy can be obtained from the primary tumor
site (i.e. breast). Tumor tissue from bone metastases is not acceptable. If fresh
biopsy from metastatic tumor or primary tumor site is not possible, archival tumor
tissue (formalin-fixed paraffin embedded [FFPE] or tumor block) may be used as long as
it is from within 12 months of study entry. NOTE: If tissue is not available within
required timeframe (i.e., either fresh or archival) subject will still be eligible for
Willing to undergo fresh biopsy of the primary tumor prior to day 1 of treatment for
research purposes (breast is preferred; lymph node is acceptable). If not clinically
feasible, then provide archived tumor tissue (FFPE or tumor block) of the primary
tumor within 12 months of study entry. If archived tissue will be submitted rather
than fresh biopsy, the archived tissue must be assessed and documented by pathology to
ensure adequate tumor is present for correlative analysis. NOTE: For subjects who do
not have archival tumor tissue available within required timeframe or if archival
tissue insufficient, a pre-treatment core biopsy of the primary breast tumor must be
obtained. If subjects have inflammatory breast cancer and a core biopsy is not
possible, consideration can be given to obtain a skin punch biopsy.
6. Demonstrate adequate organ function as defined in the table below; all screening labs
to be obtained within 14 days prior to day 1 of treatment.
- Absolute Neutrophil Count (ANC): greater than or equal to 1,000/µL
- Platelet Count greater than or equal to 100,000/µL without platelet transfusion
within 4 weeks of day 1 of treatment
- Hemoglobin (Hgb): greater than or equal to 9 g/dL without red blood cell
transfusion within 4 weeks of day 1 of treatment
- Serum creatinine (SCr): less than or equal to 1.5 × upper limit of normal (ULN)
7. For subjects anticipated to receive anthracyclines, adequate cardiac function as
defined by ≥50% Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA within 28
days prior to day 1 of treatment.
8. Females of childbearing potential (FCBP) must have a negative serum pregnancy test
within 7 days prior to day 1 of treatment and documented. NOTE: Females are considered
of childbearing potential unless they are surgically sterile (have undergone a
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or are
postmenopausal (>45 years of age and at least 12 consecutive months with no menses
without an alternative medical cause).
9. FCBP must be willing to use a highly effective contraceptive method (i.e., highly
effective achieves a failure rate of <1% per year when used consistently and
correctly) or a combination method from the time of informed consent until 30 days
after treatment discontinuation. Contraceptive methods with low user dependency are
preferable but not required.
Acceptable methods of contraception (highly effective) are:
Single method (one of the following is acceptable):
- Non-hormonal Intrauterine device (IUD)
- Vasectomy of a female subject's partner
- Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk
associated with the study treatments.
Combination method (requires use of two of the following):
- Diaphragm with spermicide (Cannot be used in conjunction with cervical
- Cervical cap with spermicide (nulliparous women only)
- Contraceptive sponge with spermicide (nulliparous women only)
- Male condom or female condom (cannot be used together) with spermicide
10. Male subjects with female partners who are of child-bearing potential, should use a
highly effective method of contraception during niraparib therapy and for 90 days
after receiving the last dose of niraparib.
11. Subjects must agree to not donate blood for 90 days after receiving the last dose of
12. Female subjects must agree to not breastfeed during the study or for 30 days after the
last dose of study treatment and male subjects must not donate sperm during niraparib
therapy and for 90 days after receiving the last dose of niraparib.
13. As determined by the enrolling physician, ability of the subject to understand and
comply with study procedures for the entire length of the study.
14. Ability to swallow oral medications.
Stage 1 Exclusion Criteria
Subjects meeting any of the criteria below may not participate in Stage 1 of the study:
1. Subject has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Note: Subjects with previously treated brain metastases may participate if
there is no evidence of disease progression for at least 4 weeks after CNS-directed
treatment as ascertained by clinical examination and brain imaging (MRI or CT) during
the screening period, are asymptomatic, have no requirement for steroids, no
requirement for anticonvulsants, and stable CNS radiographic study showing no
significant vasogenic edema ≥ 4 weeks since completion of radiation and ≥ 1 week since
discontinuation of steroids. Carcinomatous meningitis precludes a subject from study
participation regardless of clinical stability.
2. More than 3 prior lines of chemotherapy for triple-negative metastatic disease.
3. Not recovered (i.e., ≥ Grade 1) from adverse events due to agents previously
administered; NOTE: Subjects with ≤ Grade 2 neuropathy or alopecia of any grade are an
4. Prior chemotherapy within 3 weeks, prior targeted small molecule therapy or radiation
therapy within 2 weeks, or prior anti-cancer monoclonal antibody for direct
anti-neoplastic treatment within 3 weeks prior to day 1 of treatment.
5. History or known allergic reaction to doxorubicin, cyclophosphamide, paclitaxel or
6. For Arm 1, any prior anthracycline exposure.
7. For Arm 2, prior doxorubicin exposure of > 300 mg/m2 or equivalent anthracycline
exposure (i.e. epirubicin dose > 540 mg/m2).
Stage 2 Exclusion Criteria
Subjects meeting any of the criteria below may not participate in Stage 2 of the study:
1. Final needle aspirate (FNA) alone to diagnose primary breast cancer.
2. Excisional biopsy or lumpectomy performed prior to screening.
3. Surgical axillary staging procedure prior to screening; NOTE: the following procedures
are permitted prior to screening:
1. FNA or core biopsy of an axillary node for any subject
2. Although not recommended, a pre-neoadjuvant therapy sentinel node (SN) biopsy for
subjects with clinically negative axillary nodes
4. Definitive radiologic evidence of metastatic disease.
5. History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral
ductal carcinoma in-situ (DCIS) treated with radiotherapy (NOTE: subjects with a
lobular CIS (LCIS) are eligible).
6. Treatment including chemotherapy, radiation, and/or targeted therapy administered for
the currently diagnosed breast cancer prior to screening.
7. Previous therapy with anthracyclines for any malignancy.
8. History of known allergic reaction to doxorubicin or cyclophosphamide.
Overall Exclusion Criteria
Subjects meeting any of the criteria below may not participate in the study:
1. Active infection requiring systemic therapy (NOTE: at discretion of investigator,
subjects with uncomplicated urinary tract infections may be eligible).
2. Major surgery within 3 weeks of day 1 of treatment.
3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
4. Has had diagnosis, detection or treatment of another type of cancer ≤ 2 years prior to
day 1 of treatment (exceptions include basal cell or squamous cell skin cancer, or
in-situ cervical cancer that has been definitively treated).
5. Known hypersensitivity to the components of niraparib or the excipients.
6. Prior treatment with any PARP inhibitor.
7. Has received any other investigational agents within 4 weeks of day 1 of treatment or
within a time interval less than at least 5 half-lives of the investigational agent,
whichever is longer, prior to day 1 of treatment.
8. Has a known history of Human Immunodeficiency Virus (HIV) or known acquired
immunodeficiency disorder (AIDS).
9. Known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid
10. Poor medical risk as evidenced by uncontrolled intercurrent illness including, but not
limited to, uncontrolled hypertension, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, recent (within 90 days) myocardial infarction;
uncontrolled major seizure disorder; unstable spinal cord compression; superior vena
cava syndrome; or any psychiatric or substance abuse disorders or psychiatric
illness/social situations that would limit compliance with study requirements as
determined by the investigator.
11. Received a transfusion (platelets or red blood cells) ≤ 4 weeks of day 1 of treatment.
12. Subject has a condition (such as transfusion dependent anemia or thrombocytopenia)
that might confound the results of the study or interfere with the subject's
participation for the full duration of the study treatment or that makes it not in the
best interest of the subject to participate.