Clinical Trials /

Niraparib in Combination With Trastuzumab in Metastatic HER2+ Breast Cancer

NCT03368729

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Niraparib in Combination With Trastuzumab in Metastatic HER2+ Breast Cancer
  • Official Title: A Phase 1b/2 Study of the PARP Inhibitor Niraparib in Combination With Trastuzumab in Patients With Metastatic HER2+ Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: F2017000 (UAB 17112)
  • NCT ID: NCT03368729

Conditions

  • Metastatic Breast Cancer
  • HER2 Positive Breast Carcinoma

Interventions

DrugSynonymsArms
Niraparibformerly MK-4827Phase 1: 300 mg/kg Niraparib + 6 mg/kg Trastuzumab
TrastuzumabPhase 1: 300 mg/kg Niraparib + 6 mg/kg Trastuzumab

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1: 300 mg/kg Niraparib + 6 mg/kg TrastuzumabExperimentalIn phase 1 patients in this first arm will receive 300 mg/kg Niraparib in combination with 6 mg/kg Trastuzumab given IV every 3 weeks.
  • Niraparib
  • Trastuzumab
Phase 1: 200 mg/kg Niraparib + 6 mg/kg TrastuzumabExperimentalIn phase 1 patients in this second arm will receive 200 mg/kg Niraparib in combination with 6 mg/kg Trastuzumab given IV every 3 weeks.
  • Niraparib
  • Trastuzumab
Phase 2: 200 or 300 mg/kg Niraparib + 6 mg/kg TrastuzumabExperimentalThe dosage of Niraparib in phase 2 will be determined by the response of patients in Phase 1. A dosage of 300 mg/kg Niraparib will be given along with 6 mg/kg Trastuzumab IV unless a dose limiting toxicity occurs in Phase 1. If so, 200 mg/kg Niraparib will be given with the 6 mg/kg Trastuzumab (instead of 300 mg/kg Niraparib.)
  • Niraparib
  • Trastuzumab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Dose-limiting toxicity (DLT)
Time Frame:Baseline to 6 weeks
Safety Issue:
Description:A DLT is defined as hematological events > or equal to grade 3 leukopenia, anemia, and thrombocytopenia and also non-hematological events > or equal to grade 3 fatigue, nausea, constipation, vomiting, or diarrhea.

Secondary Outcome Measures

Measure:Number of adverse events
Time Frame:Baseline up to 100 weeks
Safety Issue:
Description:Toxicities will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03.
Measure:Progression-free survival
Time Frame:Baseline to the date of first documented progression to date of death from any cause, whichever comes first, assessed up to 100 months
Safety Issue:
Description:The RECIST v. 1.1 criteria will be used to evaluate progression-free survival as well as CT and MRI scans. Progression is indicative of existing target and non-target lesions.
Measure:Phase 1: Niraparib levels
Time Frame:Baseline to 25 days
Safety Issue:
Description:Plasma niraparib levels will be assessed at specific time points in participants blood during cycle 2 treatment in Phase I patients only. A population pharmacokinetic modeling approach will be used to describe area under the curve (AUC) plasma concentrations of niraparib and its metabolites in participants in this study.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Alabama at Birmingham

Trial Keywords

  • metastatic breast cancer
  • HER2 positive
  • Poly (ADP-Ribose) polymerase (PARP)
  • Niraparib
  • Trastuzumab

Last Updated

January 25, 2018