This study is designed to evaluate the efficacy and safety of first-line treatment ribociclib
in combination with aromatase inhibitor (AI) or paclitaxel with / without bevacizumab in
patients with HR-positive, HER2-negative advanced breast cancer with visceral metastasis.
Half of the patients will receive a combination of ribociclib and AI while the other half
will receive paclitaxel +/- bevacizumab.
This is a prospective, randomized, open-label, two-arm, multicenter, interventional phase III
trial in Germany. The study will include adult, postmenopausal women with HR-positive,
HER2-negative advanced breast cancer with visceral metastases, who received no prior therapy
for advanced disease.
160 patients will be enrolled and randomized 1:1 (stratified by the presence of lung and / or
liver metastases) to receive Arm A: a combination of ribociclib and AI; OR Arm B: paclitaxel
Treatment will be continued until disease progression, intolerable toxicity or death.
Progression-free survival (PFS) will be based on tumor assessments by local
radiologists/investigator using RECIST v1.1 criteria. Treatment might be continued beyond
RECIST-defined progressive disease (PD) in case of negligible or clinically irrelevant
disease progression according to the investigator's discretion until clinically relevant
disease progression or symptomatic deterioration.
- Age ≥ 18 years.
- Postmenopausal women
- Locally confirmed diagnosis of metastatic adenocarcinoma of the breast without prior
systemic antineoplastic therapy in the palliative setting.
- Hormone receptor (HR)-positive disease, defined as estrogen receptor (ER)-positive
and/or progesterone receptor (PgR)-positive.
- Human epidermal growth factor receptor 2 (HER2)-negative disease (defined as
immunohistochemistry (IHC) status HER2 negative/+ or IHC HER2++ with chromosomal in
situ hybridization (CISH)/fluorescent in situ hybridization (FISH) negative).
- Presence of visceral metastases (additional non-visceral metastases are allowed).
- Presence of target and / or non-target lesions according to RECIST v1.1
- Patients eligible for palliative treatment with AI + ribociclib and paclitaxel +/-
bevacizumab according to the respective summary of product characteristics (SmPCs).
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Adequate organ and bone marrow function within 7 days prior to randomization.
- Standard 12-lead ECG values: QT Interval Corrected by the Fridericia Correction
Formula (QTcF) interval at screening < 450 msec; Mean resting heart rate 50-90 bpm
(determined from the ECG)
- Signed written informed consent prior to beginning of protocol-specific procedures.
- Any prior systemic palliative therapy
- Prior treatment with any cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
- Prior adjuvant therapy with AI if last intake within 12 months prior to entering the
- Prior adjuvant or neoadjuvant taxane therapy if last application within 12 months
prior to entering the study.
- Patient is concurrently using other anti-cancer therapy.
- Patient has had major surgery within 28 days prior to randomization or has not
recovered from major side effects or wound is not fully recovered.
- Patient has received extended-field radiotherapy ≤ 4 weeks or limited-field
radiotherapy ≤ 2 weeks prior to randomization.
- Known hypersensitivity to ribociclib, AI, paclitaxel, bevacizumab or any of their
excipients, or against peanut, soya, Chinese hamster ovarian cell products or
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality (e.g. history of myocardial infarction within 6 months prior study entry,
long QT syndrome, clinically significant cardiac arrhythmias or systolic blood
pressure > 140 or < 90 mmHg or diastolic blood pressure > 90 mmHg).
- Patient has history of arterial thrombosis within 12 months prior to entering the
- Patient has proteinuria (≥ 2+ on urine dipstick)
- Patient with congenital bleeding diathesis, acquired coagulopathy or under full dose
- Patient is currently receiving strong inducers or inhibitors of CYP3A4/5 or medication
with narrow therapeutic window that are predominantly metabolized through CYP3A4/5 and
cannot be discontinued 7 days prior to start of study treatment.
- Known presence of cerebral metastases unless at least 4 weeks from prior therapy
completion (including radiation and/or surgery) to starting the study treatment and
clinically stable central nervous system tumor at the time of screening.
- Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH), or fondaparinux is allowed.
- Patient is currently receiving or has received systemic corticosteroids or other
chronic immunosuppressive therapy ≤ 2 weeks prior to starting study drug.
- Patients with advanced symptomatic, visceral spread, that are at risk of
lifethreatening complications in the short term (including patients with massive
uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and
over 50% liver involvement).
- Patient has a known history of HIV infection (testing not mandatory).
- Patient has active untreated or uncontrolled fungal, bacterial or viral infection.
- Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
patient participation in the clinical study or compromise compliance with the protocol
(e.g. chronic pancreatitis, chronic active hepatitis, etc.).
- Participation in prior investigational studies within 30 days prior to randomization
or within 5-half lives of the investigational product, whichever is longer.