| Eligibility |
Inclusion Criteria:
1. Women aged 18 or more
2. Histologically-confirmed advanced breast cancer (metastatic or locally advanced)
3. Progressive patients who are eligible to a treatment with capecitabine: after failure
to taxanes (neoadjuvant, adjuvant or metastatic setting) and failure to prior
anthracycline-based chemotherapy (unless contraindicated)
4. Tumor no overexpressing HER2 (HER2 1+ in IHC, or IHC 2+ and FISH/ CISH negative) in
samples from the primary and/or secondary tumor
5. A representative tumor specimen must be available for future research programs. An
archival tumor sample may be submitted; however, if one is not available, a newly
obtained tumor biopsy specimen must be submitted instead
6. Measurable or evaluable disease according to RECIST v1.1 criteria
7. Patients must be able to swallow tablets and capsules
8. Patients must have an estimated survival of at least 3 months
9. WHO performance status (ECOG) from 0 to 1
10. Adequate hematological and coagulation function: Hb = 9.0 g/dL, ANC = 1500/mm³
platelets = 100 000/mm³, INR = 1.5
11. Adequate hepatic function: total bilirubin = ULN, or total bilirubin = 3.0 x ULN or
direct bilirubin = 1.5 x ULN in patients with well documented Gilbert's Syndrome, ALAT
and ASAT = 2.5 x ULN (regardless of the presence or absence of liver metastasis)
12. Adequate renal function: serum creatinine = 1.5 mg/dL or creatinine clearance = 50
mL/min
13. Adequate ionic balance: potassium, total calcium (corrected for serum albumin),
magnesium, sodium and phosphorus within normal limits for the institution or corrected
to within normal limits with supplements before first dose of study medication
14. Women of child-bearing potential must agree to use an effective contraceptive method
while on treatment and for 8 weeks after study drugs discontinuation. Highly effective
contraception methods are detailed in section 6.1.1.
15. Patient must be affiliated to a Social Security system
16. Patient information and written informed consent form signed
Exclusion Criteria:
1. Patient has been pre-treated by CDK inhibitor or capecitabine
2. Patient has a DPD deficiency
3. Patient has a known hypersensitivity to to 5-FU or to any of the excipients of
ribociclib or capecitabine
4. Patients with central nervous system (CNS) involvement unless they meet ALL of the
following criteria:
- At least 4 weeks from prior therapy completion (including radiation and/or
surgery) to starting the study treatment
- Clinically stable CNS tumor at the time of screening and not receiving steroids
and/or enzyme-inducing anti-epileptic medications for brain metastases
5. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of the study drugs (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)
6. Patient has a known history of HIV infection (testing not mandatory)
7. Clinically significant, uncontrolled heart disease and/or recent events including any
of the following:
- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 12 months prior to screening
- History of documented congestive heart failure (New York Heart Association
functional classification III-IV)
- Documented cardiomyopathy
- Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
- History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
arrhythmias, or conduction abnormality within 12 months of screening
- Congenital long QT syndrome or family history of long QT syndrome
- Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening
- Bradycardia (heart rate <50 at rest), by ECG or pulse, at screening
8. On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or
not interpretable) or QTcF >450 msec (using Fridericia's correction). All as
determined by screening ECG (mean of triplicate ECGs)
9. Patient is currently receiving any of the following medications (see Table 9 for
details) and cannot be discontinued 7 days prior to starting study drugs:
- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit,
grapefruits hybrids, pummelos, star-fruit, and Seville oranges
- That have a narrow therapeutic window and are predominantly metabolized through
CYP3A4/5
- That have a known risk to prolong the QT interval or induce Torsades de Pointes
- Herbal preparations/medications, dietary supplements
10. Patient is currently receiving or has received:
- systemic corticosteroids within = 2 weeks prior to starting study drug, or who
have not fully recovered from side effects of such treatment. The following uses
of corticosteroids are permitted: single doses, topical applications (e.g., for
rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or
local injections (e.g., intra-articular)
- sorivudine or brivudine within 4 weeks prior to starting capecitabine
11. Patients with concurrent severe and/or uncontrolled concurrent medical conditions that
would, in the investigator's judgement, cause unacceptable safety risks,
contraindicate the participation in the study or compromise compliance with the
protocol (e.g., uncontrolled hypertension and/or uncontrolled diabetes mellitus,
clinically significant pulmonary disease, clinically significant neurological
disorder, chronic pancreatitis, chronic active hepatitis, active untreated or
uncontrolled fungal, bacterial or viral infections, etc.)
12. Patient is currently receiving warfarin or other coumarin-derived anticoagulant for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH) or fondaparinux is allowed
13. Participation in a prior investigational study within 30 days prior to enrolment or
within 5 half-lives of the investigational product, whichever is longer
14. Patient who has received radiotherapy = 4 weeks or limited field radiation for
palliation = 2 weeks prior to starting study drug, or who has not recovered to grade 1
or better from related side effects of such therapy (exceptions include alopecia)
and/or in whom = 25% of the bone marrow was irradiated
15. Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects (tumor biopsy is not considered as major surgery)
16. Patient has not recovered from all toxicities related to prior anticancer therapies to
NCI-CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with any grade
of alopecia are allowed to enter the study)
17. Patient with a Child-Pugh score B or C
18. Patient has a concurrent malignancy or malignancy within 3 years of inclusion, with
the exception of adequately treated, basal or squamous cell carcinoma,
non-melanomatous skin cancer or curatively resected cervical cancer
19. Patient has a history of non-compliance to medical regimen or inability to grant
consent
20. Pregnant (confirmed by a positive hCG laboratory test > 5mIU/mL) or lactating women
21. Any condition which in the investigator's opinion makes it undesirable for the subject
to participate in the trial or which would jeopardize compliance with the protocol
22. Individuals deprived of liberty or placed under the authority of a tutor
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