Niraparib Plus Aromatase Inhibitors for Luminal-like(HER2-,ER+) and gBRCA or HDR+ Metastatic Breast Cancer (LUZERN)

Study Overview
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Brief Summary
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This study evalues the efficacy -as determined by the clinical benefit rate (CBR)- of niraparib in combination with AIs in unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer patients harboring either gBRCAms or gBRCAwt and HRD. The planned number of patients is 23. Investigational product is Niraparib 100 mg and the study dose will be 200mg or 300mg daily continuously in 28-day cycles plus aromatase Inhibitors. Total study duration is 36 months and until 5 years of follow up.

Detailed Description
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This is a Multicenter, Open-label, Phase II Clinical Trial to Evaluate the Efficacy and Safety of Niraparib plus Aromatase Inhibitors for Hormone Receptor (HR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-negative Metastatic Breast Cancers with either Germline BRCA-mutated or Germinal BRCA-wild-type and Homologous Recombination Deficiency (HRD). The main objetive is to assess the efficacy -as determined by the clinical benefit rate (CBR)- of niraparib in combination with AIs in unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer patients harboring either gBRCAms or gBRCAwt and HRD. Upon meeting all selection criteria, patients enrolled in the study will receive the combination of niraparib either 300 mg or 200 mg orally (according to baseline criteria described in Table 4), once daily, flat- fixed, continuously in 28-day cycles and AI that must be identical to the last AI-containing regimen. A total of 23 patients will be recruited as follows: Stage I: N=6 patients in the cohort A; Stage II: N=8 patients in the cohort A; N=9 patients in the exploratory cohort B The total duration of the study period is 36 months follow until 5 years of follow up.

Official Title
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Multicenter,Open-label,Phase II Clinical Trial to Evaluate the Efficacy and Safety of Niraparib + Aromatase Inhibitors for(HR)+/(HER2)-, MBC With Either Germline BRCA-mutated or Germinal BRCA-wildtype and Homologous Recombination Deficiency

Conditions
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Breast Cancer, Breast Cancer Metastatic

Intervention / Treatment
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* Drug: Niraparib 100 MG
* Drug: Aromatase Inhibitors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Patients have been informed about the nature of study, including the exploratory sub-study and has agreed to participate and signed the informed consent prior to participation in any study- related activities. 2. Male or female patients ≥ 18 years of age. 3. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 which the Investigator believes is stable at the time of screening. 4. Life expectancy ≥16 weeks. 5. Patients have a histologically and/or cytologically confirmed diagnosis of breast cancer. 6. Patients have radiologic evidence of inoperable locally recurrent or metastatic breast cancer (MBC) that are not candidates for curative intent. 7. Patients have human epidermal growth factor receptor 2 (HER2)- negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization (ISH) test or an immunohistochemistry (IHC) status of 0, 1+, or 2+ (if IHC 2+, a negative ISH test is required) by local laboratory testing. 8. Patients have hormone receptor (HR)-positive breast cancer (based on most recently analyzed biopsy) defined as estrogen receptor (ER) and/or progesterone receptor (PgR) with ≥10% of tumor cells positive for ER and/or PgR by IHC irrespective of staining intensity. 9. [Cohort A]: Patients with documented germinal mutation in BRCA1 or BRCA2 genes that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). 10. [Exploratory cohort B]: Patients with either germinal BRCA1/2 wild-type (gBRCAwt) or gBRCAms that are considered to be non- detrimental and homologous recombination deficiency (HRD) based on the HRDetect predictor test. 11. [Exploratory cohort B]: Willingness and ability to provide additional six formalin-fixed paraffin-embedded (FFPE) tissue slides from the most recent tumor tissue since last progression (from either metastasis or primary tumor) to centrally perform the RAD51 assay. 12. At least one and up to two prior lines of endocrine therapy (aromatase inhibitors [AIs] or fulvestrant) for treatment of locally recurrent and/or metastatic disease (except for patients progressing in the neoadjuvant or adjuvant setting). 13. Confirmed disease progression while in the last AI-containing regimen (not necessarily in the treatment line immediately prior to study entry) with secondary endocrine resistance criteria. 14. Patients may have progressed on no more than one chemotherapy regimens in the metastatic setting. 15. The following will not be counted as a prior line of cytotoxic chemotherapy: Prior hormonal therapy and non-hormonal targeted therapy. Targeted and biologic therapies. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as this was started at least 5 days prior to study treatment. 16. Prior carboplatin- or other platinum compound-based therapy is allowed if have been administered in one of the following settings: Disease-free interval > 12 months from date of completion of neoadjuvant or adjuvant treatment. As potentially curative treatment for a prior non-breast cancer with no evidence of disease for ≥ 5 years. 17. Patients must have evaluable or measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. Patient with bone-only metastases are eligible. 18. Willingness and ability to provide the most recent tumor biopsy since last progression from either metastatic or primary tissues both at the time of the inclusion and at disease progression or study termination in order to perform exploratory studies. 19. Patients must agree to provide blood samples at the time of study inclusion, every three cycles of treatment, and upon disease progression or study termination in order to perform exploratory studies. 20. Adequate hematologic and organ function within 28 days before the first study treatment on Cycle 1 Day 1. 21. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to study treatment and must agree to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment. 22. Female patients must agree not to breastfeed during the study and for 180 days after the last dose of study treatment. 23. Male patients whose partners are women of childbearing potential must use a condom during niraparib therapy and for 90 days after receiving the last dose of niraparib. Exclusion Criteria: 1. HER2-positive disease based on local laboratory results (performed by IHC/in situ hybridization test) or unknown HER2 status. 2. Patients that are candidates for a local treatment with a radical intention. 3. Patients that have previously received any PARP inhibitor (PARPi), including niraparib, in metastatic setting. 4. Patients must not be simultaneously enrolled in any interventional clinical trial and 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. 5. Patients who have had radiation therapy encompassing >20% of the bone marrow within 2 weeks prior to start of treatment, excepting for palliative radiation therapy to a small field >1 week prior to Day 1 of study. 6. Patients with visceral crisis who require chemotherapy. 7. Patients must not have a known hypersensitivity to niraparib components or excipients. 8. Patients must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy. 9. Patients must not have received colony-stimulating factors (e.g., Granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy. 10. Patients have had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy in adjuvant setting or cyclin-dependent kinases (CDK)4/6 inhibitors that persisted > 4 weeks and was related to the most recent treatment. 11. Patients must not have any known history of Myelodysplastic syndrome (MDS) or Acute myeloid leukemia (AML). 12. Patients must not have a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. 13. Patients must not have had diagnosis, detection, or treatment of another type of cancer ≤ 2 years prior to initiating protocol therapy. 14. Patients with symptomatic uncontrolled brain metastases or leptomeningeal metastases. 15. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). 16. Patients who are unable to swallow orally administered medication. 17. Patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 18. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day methylprednisolone equivalent (excluding inhaled steroids), except for prophylaxis use. 19. Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Multicenter, open-label, single-arm, two-cohort, Simon's two- stage phase II clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Niraparib 100mg in combination with Aromatase Inhibitors<br>Upon meeting all selection criteria, patients enrolled in the study will receive the combination of niraparib either 300 mg or 200 mg orally, once daily, flat- fixed, continuously in 28-day cycles plus aromatase Inhibitors. | Drug: Niraparib 100 MG<br>* Niraparib 200 or 300 mg daily (orally) beginning on Day 1 and continuing through Day 28 of every 28-day cycle.<br>* Other names: ZEJULA;Drug: Aromatase Inhibitors<br>* Aromatase Inhibitors beginning on Day 1 and continuing through Day 28 of every 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate (CBR) of niraparib in combination with AIs in unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer patients harboring either gBRCAms or gBRCAwt and HRD | The CBR as best response, defined as the percentage of patients who experience a complete response, partial response or stable disease for at least 24 weeks and assessed by modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria | Baseline up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy determinated by the Progression-free Survival (PFS) | PFS is defined as the time from the date of the first dose of study treatment until the first documented PD based on RECIST v1.1. or death due to any cause, whichever occurs first based on local investigator's assessment according to RECIST criteria v1.1. | Baseline up to 36 months | 
| Efficacy determinated by the Objective Response Rate (ORR) | The ORR is defined as the number of patients with CR and PR divided by the number of patients in the analysis set. Tumor response will be defined as best response based on local investigator's assessment according to RECIST criteria v.1.1. | Baseline up to 36 months | 
| Efficacy determined by Duration of Response (DoR) | DoR is defined as the time from first documented CR or PR until disease progression or death from any cause, based on local investigator's assessment according to RECIST criteria v1.1. | Baseline up to 36 months | 
| Efficacy determined by Overall survival (OS) | OS is defined as the time from the date of first dose of study treatment until death by any cause or the last date the patient was known to be alive. | Baseline up to 36 months | 
| Efficacy determined by Time to response (TTR) | Time to response (TTR) is defined as the time from the date of first dose of study treatment to the first objective tumor response observed for patients who achieved a Complete response (CR) or parcial response (PR). | Baseline up to 36 months | 
| Incidence of treatment-related AEs Grade 3 and 4 and serious adverse events (SAEs) [Safety] | Safety will be measured by using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. | Baseline up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA mutations, homologous recombination deficiency, Luminal like