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PARP Inhibitor (Niraparib) and Trastuzumab for the Treatment of Metastatic HER2+ Breast Cancer

Trial Status: Active

This phase Ib / II trial studies the side effects and best dose of niraparib when given together with trastuzumab and to see how well it works in treating patients with HER2+ breast cancer that has spread to other places in the body (metastatic). The HER2 is a type of gene that regulates cell growth and survival but can be mutated into a gene that causes cancer. PARPs are proteins that help repair deoxyribonucleic acid (DNA) mutations. PARP inhibitors, such as niraparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Trastuzumab is a form of targeted therapy because it attaches itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Giving niraparib and trastuzumab together may help to improve survival with few side effects in patients diagnosed with HER2+ metastatic breast cancer.

Inclusion Criteria

  • Eastern Cooperative Oncology Group performance status 0-2 (Karnofsky > 90%)
  • Patients with metastatic breast cancer
  • HER2-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 in situ hybridization (ISH) (defined by ISH 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 RECIST v 1.1
  • Patients that have failed at least 1 anti-HER2 therapy in the metastatic setting
  • Absolute neutrophil count >= 1,500/mL
  • Platelets >=100,000/mL
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (=< 2.0 in patients with known Gilberts syndrome) OR direct bilirubin =< 1 x ULN
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN unless liver metastases are present, in which case they must be 5 =< x institutional ULN
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation
  • Baseline left ventricular ejection fraction (LVEF) >= 50% measured by echocardiogram (ECHO) (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
  • Patient receiving corticosteroids may continue as long as their dose is stable for at least 2 weeks prior to initiating protocol therapy
  • Patient must agree to not donate blood during the study or for 90 days after the last dose of study treatment
  • Female participant has a negative serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment or is of nonchildbearing potential. Nonchildbearing potential is defined as follows (by other than medical reasons): * >= 45 years of age and has not had menses for > 1 year * Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. Information must be captured appropriately within the site’s source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for 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 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
  • Required washouts from prior therapy: * 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 radiation therapy (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 leptomeningeal disease * 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 magnetic resonance imaging (MRI) or computed tomography (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. Leptomeningeal disease precludes a patient from study participation regardless of clinical stability
  • Concurrent anti-cancer treatment of any type
  • Patient must not have received investigational therapy =< 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy
  • 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/m^2 (or equivalent)
  • Patient has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [HCV RNA] [qualitative] is detected)
  • Patient has a known history of human immunodeficiency virus (HIV)
  • Patient with known hypersensitivity to niraparib components or excipients
  • 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)
  • Patient must not have had major surgery =< 3 weeks prior to initiating protocol therapy and patient must have recovered from any surgical effects
  • Patient must not have received a transfusion (platelets or red blood cells) =< 4 weeks prior to initiating protocol therapy
  • Patient must not have received colony-stimulating factors (e.g., granulocyte colony- stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy
  • Patient has had any known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment
  • Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
  • Cardiopulmonary dysfunction as defined by any of the following prior to: registration: * History of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 5.0) 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) * Requirement for oxygen therapy


University of Alabama at Birmingham Cancer Center
Status: ACTIVE
Contact: Erica M. Stringer-Reasor
Phone: 205-975-2816


University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Rita Nanda
Phone: 773-834-2756

New York

Montefiore Medical Center-Einstein Campus
Status: ACTIVE
Contact: Jesus Del Santo Anampa Mesias


Fred Hutch / University of Washington Cancer Consortium
Status: ACTIVE
Contact: Natasha Hunter
Phone: 206-606-2298


I. To determine the dose-limiting toxicity (DLT) of combination treatment of niraparib tosylate monohydrate (niraparib) and trastuzumab during the first 2 cycles of treatment and to establish a recommended phase II dose (RP2D). (Phase 1)

II. To evaluate the clinical activity of combination treatment with niraparib and trastuzumab in terms of objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. (Phase 2)


I. To determine the safety and tolerability of combination treatment with niraparib and trastuzumab using the Common Terminology Criteria for Adverse Events (CTCAE, v. 5.0).

II. To describe the toxicities seen with niraparib and trastuzumab combination therapy.

III. Progression-free survival (PFS) per RECIST v 1.1.

IV. To evaluate pharmacokinetics (PK) of niraparib and trastuzumab during combination therapy.


I. To identify differential expression and localization of PARP1, p65, phosphor-p65 in HER2+ breast cancers before and after exposure to the PARP inhibitor niraparib.

II. To evaluate markers of apoptosis and DNA damage before and after exposure to the PARP inhibitor niraparib.

III. To correlate the expression of NF-kB target genes with apoptosis markers.

IV. To assess let-7a micro ribonucleic acid (miRNA) levels.

V. To assess circulating tumor DNA for a predictive response to therapy.

OUTLINE: This is a phase Ib, dose-escalation study of niraparib followed by a phase II study.

Patients receive niraparib orally (PO) once daily (QD) on days 1-21 and trastuzumab intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 6 months for 2 years, and then annually for a total of 5 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Alabama at Birmingham Cancer Center

Principal Investigator
Erica M. Stringer-Reasor

  • Primary ID UAB17112
  • Secondary IDs NCI-2020-07859
  • ID NCT03368729