| Eligibility |
Inclusion Criteria:
1. Women or men aged 18 or more
2. Histologically-confirmed advanced breast cancer (metastatic or locally advanced)
3. Tumor without overexpression of HER2 (HER2 1+ in IHC, or IHC 2+ and FISH/ CISH
negative) in samples from the primary and/or secondary tumor
4. Hormone receptor status known
5. Endocrine insensitive (hormone receptor negative or Endocrine (aromatase
inhibitor)-resistant (a CDK4/6-based endocrine treatment must have been administered
as a first-line of second-line treatment, unless primary endocrine-refractory disease
as defined as relapse within the first 2 years of aromatase-based adjuvant endocrine
therapy or progression under endocrine treatment administered for metastatic disease
within 6 months of initiation))
6. Progressive disease patients who are eligible to a treatment with capecitabine: after
fail-ure to taxanes and anthracycline-based chemotherapy (unless contraindicated)
(neoadjuvant, adjuvant or metastatic setting)
7. A representative tumor specimen must be available for molecular testing. An archival
tu-mor sample may be submitted (<6 months); however, if one is not available, a newly
obtained tumor biopsy specimen must be submitted instead
8. Measurable disease according to RECIST1.1
9. Symptomatic, untreated, or actively progressing central nervous system (CNS)
metasta-ses are not eligible. Patients with a history of treated CNS lesions are
eligible, provided all of the following criteria are met:
1. Measurable or non-measurable disease, per RECIST v. 1.1, must be present outside
the CNS
2. No history of intracranial haemorrhage or spinal cord haemorrhage
3. Metastases are limited to the cerebellum or the supratentorial region (i.e., no
metasta-ses to the midbrain, pons, medulla, or spinal cord).
4. There is no evidence of interim progression between completion of CNS-directed
ther-apy and the screening brain scan.
5. The patient has not received stereotactic radiotherapy within 7 days prior to
initiation of study treatment or whole-brain radiotherapy within 14 days prior to
initiation of study treatment.
6. The patient has no ongoing requirement for corticosteroids as therapy for CNS
disease. Anticonvulsant therapy at a stable dose is permitted.
Asymptomatic patients with CNS metastases newly detected at screening are eligible for the
study after receiving radiotherapy or surgery, with no need to repeat the screening brain
scan.
10. Patients must have an estimated survival of at least 3 months 11. WHO performance
status (ECOG) from 0 to 1 12. Adequate hematological and coagulation function: Hb = 10.0
g/dL, ANC = 1500/mm3 platelets = 150 000/mm3, INR = 1.5 13. Adequate hepatic function :
total serum bilirubin = 1x ULN, or total bilirubin = 2.0 x ULN with direct bilirubin within
normal range in patients with well documented Gilbert's Syndrome, ALAT and ASAT = 1.5 x ULN
14. Adequate renal function: serum creatinine = 1.5 × ULN or creatinine clearance =
60mL/min 15. Adequate ionic balance: potassium, calcium (corrected for serum albumin),
magnesium, sodium and phosphorus within normal limits for the institution 16. Participant
must have normal blood pressure or adequately treated and controlled hyperten-sion17. A
female participant is eligible if she is not pregnant or breastfeeding, and at least one of
the following conditions applies:
- Is not a woman of childbearing potential (WOCBP) OR
- Is a WOCBP and must agree to use a highly effective contraceptive method (described in
6.6.2) while on treatment and for at least 180 days after study drugs discontinuation.
18. A WOCBP must have a negative pregnancy test (highly sensitive urine test or serum
test as required by local regulations) within 72 hours before the first dose of study
treatment.
19. Male participants are eligible to participate if they agree to the following
during the interven-tion period and for at least 90 days after the last dose of study
treatment:
- Refrain from donating sperm
- Must agree to use a male condom (and should also be advised of the benefit for a
female partner to use a highly effective method of contraception as a condom may break
or leak) 20. Patient must be affiliated to a Social Security system 21. Patient
information and written informed consent form signed 22. Must be able to swallow and
retain orally administered study treatment. 23. For expansion cohort: inclusion will
be done regarding availability of homologous recom-bination status
Exclusion Criteria:
1. Prior treatment with a PARP inhibitor and capecitabine for metastatic disease,
(Patients treat-ed with these drugs in the adjuvant setting are allowed to participate
if they experienced 2 years from end of treatment and metastatic relapse)
2. Patient has a Dihydropyrimidine dehydrogenase deficiency (DPD)
3. Patients must not have received anticancer chemotherapy, targeted therapy within 2
weeks prior of the study. Endocrine therapy must have been discontinued 7 or more days
before Cycle 1 Day 1. Participant must not have had investigational therapy
administered within 4 weeks or with-in a time interval less than at least 5 half-lives
of the investigational agent, whichever is longer, prior to the first scheduled day of
dosing in this study.
4. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day 1.
Biphosphonates and denosumab are allowed.
5. Major surgery within 3 weeks prior to registration. Patients must have recovered from
earlier major surgery before registration.
6. Persistent toxicities (=NCI-CTCAE grade 2) caused by previous cancer therapy,
excluding alopecia and NCI-CTCAE grade 2 peripheral neuropathy.
7. Immunocompromised patients (e.g. HIV) for part I and but patients with well controlled
HIV could be included in part II (negative viral load)
8. Patients considered at poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection,
symptomatic congestive heart fail-ure, uncontrolled hypertension, unstable angina
pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses, or Posterior Reversible Encephalopathy Syn-drome (PRES).
9. Mean resting QT interval corrected for heart rate (QTc) =470 ms calculated from 3
consecutive electrocardiograms using Fridericia's Correction.
10. Active or prior documented inflammatory bowel disease (Crohn's disease, ulcerative
colitis).
11. Patients unable to swallow orally administered medication, patients with
gastrointestinal dis-orders likely to interfere with absorption of niraparib, and
patients with long-term oral anticoagu-lant therapy.
12. Pregnant or breast-feeding women. Participant must agree to not breastfeed during the
study and for 30 days after the last dose of study treatment
13. Known hypersensitivity to niraparib or capecitabine or any of the excipients of the
products
14. Patient is currently receiving or has received sorivudine or brivudine within 4 weeks
prior to starting capecitabine
15. Patient has received a transfusion (platelets or red blood cells) = 4 weeks prior to
initiating protocol therapy
16. Patient has received colony-stimulating factors (e.g. granulocyte colony-stimulating
factor, granulocyte macrophage colony-stimulating factor, or recombinant
erythropoietin) = 4 weeks prior to initiating protocol therapy
17. Patient has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to
prior chemotherapy that persisted > 4 weeks
18. Patient has any known history of myelodysplastic syndrome (MDS) or acute myeloid
leuke-mia (AML)
19. Patient has a diagnosis, detection, or treatment of another type of cancer = 2 years
prior to initiating study therapy with the following exceptions: basal or squamous
cell carcinoma of the skin, cervical cancer in situ that has been definitively
treated, adequately treated nonmelanoma skin cancer, ductal carcinoma in situ (DCIS)
of the breast.
20. Patient has known active hepatitis B (e.g. hepatitis B surface antigen (HBsAg]
reaction) or hepatitis C (e.g. hepatitis C virus [HCV] ribonucleic acid [qualitative]
is detected)
21. Participants have received live vaccine within 30 days of planned start of study
registration. 22. Participants have current active pneumonitis or any history of
pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days
of planned start of the study.
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