Advanced or metastatic HR-positive/HER2-negative breast cancer in patients harboring either gBRCAms or gBRCAwt and HRD. MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10070575 Term: Estrogen receptor positive breast cancer System Organ Class: 100000004864 MedDRA version: 20.1 Level: PT Classification code 10077481 Term: Human epidermal growth factor receptor negati
Conditions
Interventions
Trade Name: Zejula
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NIRAPARIB
Other descriptive name: NIRAPARIB TOSILATE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equa
Sponsors
Medica Scientia Innovation Research (MedSIR)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria: 1. Male or female patients = 18 years of age. ECOG 0-1 2. Life expectancy =16 weeks. 3. Patients have radiologic evidence of inoperable locally recurrent or metastatic breast cancer (MBC) that are not candidates for curative intent. 4. Patients have (HER2)- negative and (HR)-positive breast cancer 5. [Cohort A]: Patients with documented germinal mutation in BRCA1 or BRCA2 genes Germinal BRCA assays carried out prior to enrollment will be accepted. 6. [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. 7. [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. 8. 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). 9. Confirmed disease progression while in the last AI-containing regimen: a. Progression on adjuvant AI-based regimen, confirmed after at least 2 years of ongoing therapy and within 12 months following adjuvant treatment interruption; OR, b. Progression to at least one AI-based regimen for treatment of locally recurrent and/or metastatic disease after having achieved clinical benefit (at least 24 weeks on treatment). Confirmation of progression must be within 6 weeks after the end of treatment for locally recurrent and/or metastatic disease. 10. Patients may have progressed on no more than one chemotherapy regimens in the metastatic setting. 11. The following will not be counted as a prior line of cytotoxic chemotherapy: a. Prior hormonal therapy and non-hormonal targeted therapy. b. Targeted and biologic therapies. 12. 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. 13. Prior carboplatin- or other platinum compound-based therapy is not allowed. 14. Patients must have evaluable or measurable disease according to (RECIST) criteria version 1.1. Patient with bone-only metastases are eligible. 15. 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. 16. 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. 17. Adequate hematologic and organ function within 28 days before the first study treatment on Cycle 1 Day 1 18. 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, or patients of nonchildbearing potential. 19. Female patients must agree not to breastfeed during the study and for 180 days after the last dose of study treatment. 20. Male pati
Exclusion criteria
Exclusion criteria: Exclusion Criteria: 1. HER2-positive disease based on local laboratory results (performed by IHC/in situhybridization 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 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)4/6inhibitors 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 with symptomatic uncontrolled brain metastases or leptomeningealmetastases. 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 with gastrointestinal disorders likely to interfere with absorption of the study medication. 17. Chronic daily treatment with corticosteroids with a dose of = 10 mg/day methylprednisolone equivalent (excluding inhaled steroids), except for prophylaxis use. 18. Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: Secondary Objectives: • To assess the efficacy –as determined by the Progression-free Survival (PFS), Objective Response Rate (ORR), time to response (TTR), duration of response (DoR), overall survival (OS), and maximum tumor reduction– of niraparib in combination with AIs in these patients. • To evaluate the safety and tolerability of niraparib in combination with AIs in these patients. Exploratory Objectives: • To assess the prevalence of gBRCAms and HRD in these patients. • To evaluate predictive and/or prognostic biomarkers associated with disease activity status or patient outcomes for the combination of niraparib and AIs in these patients. • To identify possible mechanisms of resistance to the combination of niraparib and AIs through the comparative analysis of potential biomarkers from paired pre-treatment and post-progression tumor biopsies and/or blood samples in these patients.;Primary end point(s): Primary Endpoint: • CBR defined as the percentage of patients who experience a complete response (CR), partial response (PR) or stable disease (SD) for at least 24 weeks. CBR will be assessed locally by the Investigator through the use of RECIST v.1.1 criteria.;Timepoint(s) of evaluation of this end point: Time from randomization to disease progression. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoints: • The efficacy will be evaluated by PFS, ORR, TTR, DoR, OS, and maximum tumor reduction. PFS, ORR, TTR, DoR, and maximum tumor reduction will be assessed locally by the Investigator through the use of RECIST v.1.1 criteria. • The safety and tolerability will be evaluated by incidence of adverse events (AEs), prespecified AEs, change from baseline in targeted vital signs, and change from baseline in targeted clinical laboratory test results according to the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Exploratory Endpoints: • The number of patients harboring either gBRCAms (distinguishing between deleterious or suspected deleterious mutations in BRCA1 and BRCA2 genes), or gBRCAwt and HRD (distinguishing among different genomic signatures) divided by the total number of patients in the analysis set. • The number of patients harboring either gBRCAms (distinguishing between deleterious or suspected deleterious mutations in BRCA1 and BRCA2 genes), or gBRCAwt and HRD (distinguishing among different genomic signatures) who obtain clinical benefit divided by the total number of patients in the analysis set. • Association of prognostic and/or predictive, tumor- and/or immune-related biomarkers in tumor biopsies and/or blood samples with CBR, PFS, ORR, TTR, DoR, OS, and maximum tumor reduction. • Association of biomarkers indicators of drug resistance in paired pre-treatment and post-progression tumor biopsies and/or blood samples with CBR, PFS, ORR, TTR, DoR, OS, and maximum tumor reduction.;Timepoint(s) of evaluation of this end point: Time from randomization to disease progression. | — |
Countries
Spain
Contacts
Public ContactClinical Trial Unit
Medica Scientia Innovation Research (MedSIR)
Outcome results
None listed