Niraparib in Combination With Trastuzumab in Metastatic HER2+ Breast Cancer
Niraparib in Combination With Trastuzumab in Metastatic HER2+ Breast Cancer
The human epidermal growth factor receptor 2 (HER2) regulates cell growth and survival.
 Approximately 15-20% of all breast cancers are HER2-positive, which are an aggressive and
 fast-growing subtype of breast cancer. This study will evaluate a new treatment using a
 potent Poly polymerase (PARP) inhibitor known as Niraparib. Niraparib will be combined with
 trastuzumab, a HER2-targeted agent, to evaluate the safety and tolerability in patients with
 metastatic HER2 positive breast cancer. It is anticipated that the combination of drugs will
 improve survival and have few side effects.
Treatment will be administered on an outpatient basis. All patients in the phase 1 and 2
 portion of the study will receive Niraparib by mouth on days 1-21 of each 21 day cycle as
 well as trastuzumab intravenously (IV) on day 1 of each cycle. Blood and tissue will be
 collected at pre-specified times to enable pharmacokinetic, biomarker, and toxicity studies.
 The drug dosage will then be determined for the phase 2 portion at a dose limiting level.
 Following treatment, patients will be followed every 6 weeks for 6 months until disease
 progression or an unacceptable adverse event.
Inclusion Criteria:

 -  Women age ≥ 18 years

 -  Eastern Cooperative Oncology Group performance status 0-2 (Karnofsky >60%).

 -  Patients with metastatic breast cancer.

 -  HER2 (human epidermal growth factor receptor 2)-positive breast cancer prospectively
 determined on the primary tumor by a local pathology laboratory and defined as:
 Immunohistochemistry (IHC) score of 3+ and/or positive by ISH (defined by In Situ
 Hybridization ratio of ≥ 2.0 for the number of HER2 gene copies to the number of
 chromosome 17 copies). Both IHC and ISH assays will be performed; however, only one
 positive result is required for eligibility.

 -  Estrogen/progesterone receptor positive OR negative disease allowed.

 -  Patients must have measurable disease per the Response Evaluation Criteria in Solid
 Tumors (RECIST) v1.1.

 -  Patients that have failed at least one anti-HER2 therapy in the metastatic setting.

 -  Patients must have normal organ and marrow function as defined below:

 -  absolute neutrophil count ≥1,500/mL

 -  platelets ≥100,000/mL

 -  total bilirubin ≤ institutional upper limit of normal (ULN)

 -  aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 5 ≤ X
 institutional ULN

 -  creatinine ≤ institutional ULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for
 patients with creatinine levels above institutional normal.

 -  Baseline left ventricular ejection fraction (LVEF) ≥ 50% measured by echocardiogram
 (preferred) or multigated acquisition (MUGA) scans.

 -  Willing and able to comply with the requirements of the protocol.

 -  Patient is able to take oral medication.

 -  Signed informed consent.

 -  Female patients of childbearing potential must be willing to use one highly effective
 form of hormonal contraception or two effective forms of nonhormonal contraception.

 -  Contraception must continue for the duration of study treatment and for 7 months after
 the last dose of study treatment. The above contraception is not a requirement in the
 case of any of the following:

 -  The patient, or partner of the patient, is surgically sterilized.

 -  The female patient is >45 years of age and is postmenopausal (has not menstruated
 for at least 12 consecutive months

 -  The patient truly abstains from sexual activity and when this is the preferred
 option to avoid conception and contraception and/or usual lifestyle of the
 patient.

 Exclusion Criteria:

 -  Metastatic breast cancer patients who are HER2 positive and have NOT progressed on at
 least one prior HER2-targeted therapies for metastatic disease

 -  Patients who have not recovered from CTCAE, v. 4.03 grade 2 or higher toxicities of
 prior therapy to the point that they would be appropriate for re-dosing will be
 ineligible for study treatment. Subjects receiving weekly therapy must have a washout
 period from prior chemotherapy of as least one week. Washout period for chemotherapy
 administered every 2, 3, or 4 weeks will be 2, 3, and 4 weeks respectively, provided
 subject has recovered from toxicities of prior therapy such that retreatment is
 appropriate.

 -  Patients must be at least two weeks from prior RT

 -  Patients must have a one-week washout period from prior hormonal therapy (e.g.
 testosterone, estrogen, progestin, gonadotropin-releasing hormone antagonist).

 -  Patient has known active central nervous system (CNS) metastases and/or carcinomatous
 meningitis.

 Note: Patients with previously treated brain metastases may participate provided they are
 stable (without evidence of progression by imaging [using the identical imaging modality
 for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of
 study treatment and any neurologic symptoms have returned to baseline), have no evidence of
 new or enlarging brain metastases, and have not been using steroids for at least 7 days
 prior to study treatment. Carcinomatous meningitis precludes a patient from study
 participation regardless of clinical stability.

 No concurrent anti-cancer treatment of any type

 -  Patients with known germline BRCA 1 or BRCA 2 mutations

 -  Patient has undergone prior treatment with a known poly(ADP-ribose) polymerase (PARP)
 inhibitor.

 -  Prior treatment of a total doxorubicin >360 mg/m2 (or equivalent)

 -  Patient has known active hepatitis B (eg, hepatitis B surface antigen [HBsAg]
 reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [HCV RNA]
 [qualitative] is detected).

 -  Patient has a known history of human immunodeficiency virus (HIV) (HIV 1/2
 antibodies).

 -  Chronic immunosuppressive therapies including systemic corticosteroids or concurrent
 short-term use of immunosuppressive therapies is not allowed. Short- term
 corticosteroid use must be discontinued at least 2 weeks prior to study treatment.

 -  Patients with known grade 2 or greater allergic reactions attributed to compounds of
 similar chemical or biological composition to niraparib are ineligible for study
 enrollment.

 -  Patients with known grade 2 or greater allergic reactions attributed to compounds of
 similar chemical or biological composition to herceptin are ineligible for study
 enrollment.

 -  Patient is pregnant or breastfeeding, or expecting to conceive children within the
 projected duration of the study, starting with the screening visit through 7 months
 after the last dose of study treatment.

 -  History of non-breast malignancies within the 5 years prior to study entry, except for
 the following:

 -  Carcinoma in situ (CIS) of the cervix

 -  CIS of the colon

 -  Melanoma in situ

 -  Basal cell and squamous cell carcinomas of the skin

 -  Patient is considered a poor medical risk due to a serious, uncontrolled medical
 disorder, nonmalignant systemic disease or active infection that requires systemic
 therapy. Specific examples include, but are not limited to, active, non-infectious
 pneumonitis; uncontrolled major seizure disorder; unstable spinal cord compression;
 superior vena cava syndrome; or any psychiatric or substance abuse disorders that
 would interfere with cooperation with the requirements of the study (including
 obtaining informed consent).

 -  Cardiopulmonary dysfunction as defined by any of the following prior to randomization:

 -  History of National Cancer Institute Common Terminology Criteria for Adverse
 Events (NCI CTCAE; Version 4.0) Grade ≥3 symptomatic congestive heart failure
 (CHF) or New York Heart Association (NYHA) criteria Class ≥ II

 -  Angina pectoris requiring anti-angina medication, serious cardiac arrhythmia not
 controlled by adequate medication, severe conduction abnormality, or clinically
 significant valvular disease

 -  High-risk uncontrolled arrhythmias (i.e. atrial tachycardia with a heart rate
 >100/min at rest, significant ventricular arrhythmia [ventricular tachycardia],
 or higher-grade atrioventricular [AV]-block [second degree AV-block Type 2
 [Mobitz 2] or third degree AV-block])

 -  Significant symptoms (Grade ≥2) relating to left ventricular dysfunction, cardiac
 arrhythmia, or cardiac ischemia

 -  Myocardial infarction within 12 months prior to randomization

 -  Uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic
 blood pressure >100 mmHg)

 -  Evidence of transmural infarction on ECG

 -  Heart-rate corrected QT interval (QTc) prolongation >470 msec at screening.

 -  Requirement for oxygen therapy