This is a randomized trial for patients with metastatic hormone receptor (HR)-positive human
epidermal growth factor receptor 2 (HER2)-negative breast cancer who have progressed on an
aromatase inhibitor plus a CDK4/6 inhibitor (either palbociclib or ribociclib) to either
fulvestrant alone or fulvestrant with ribociclib (LEE-011). The purpose of the trial is to
determine whether there is continued benefit for patients to remain on a CDK4/6 inhibitor at
the time of switching anti-estrogen therapy. As ribociclib and palbociclib have a similar
toxicity and drug profile and mechanism of action, we feel that it is appropriate for
patients to receive either drug with an aromatase inhibitor prior to randomization.
1. Men or women at least 18 years of age with histologically or cytologically confirmed
adenocarcinoma of the breast with unresectable or metastatic disease.
2. Most recent tumor biopsy or surgical resection specimen must be either
estrogen-receptor (ER) positive, progesterone receptors (PgR) positive, or both, as
defined by immunohistochemistry (IHC) ≥1% (as per the American Society of Clinical
Oncology (ASCO)-College of American Pathologists (CAP) guidelines).
3. HER2-negative breast cancer defined as a negative in situ hybridization test or an
immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+ (i.e. indeterminate), a
negative in situ hybridization (Fluorescent in situ hybridization (FISH), Chromogenic
in situ hybridization (CISH), or Silver-enhanced in situ hybridization (SISH)) test is
required by local laboratory testing. (as per the ASCO-CAP guidelines).
4. Postmenopausal status or receiving ovarian ablation with a GnRH agonist such as
goserelin. Postmenopausal status is defined by any one of the following criteria:
- Prior bilateral oophorectomy.
- Age ≥60 years.
- Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
tamoxifen, toremifen, or ovarian suppression) and FSH, LH, and estradiol in the
postmenopausal range per local normal If the patient does not meet criteria for
postmenopausal status but is receiving ovarian ablation therapy with a
gonadotropin-releasing hormone (GnRH) agonist such as goserelin, the patient is
eligible for this study, provided that the GnRH agonist is started at least 2
weeks prior to C1D1 of anti-estrogen therapy.
5. Have evidence of measurable or unmeasurable disease.
6. Eastern Cooperative Group (ECOG) performance status of 0 or 1.
7. No prior cdk 4/6 inhibitor (Closed to Accrual). If patient has not previously received
letrozole, letrozole will be supplied by Novartis. If previously progressed on
letrozole, another aromatase inhibitor that the patient has not previoulsy received is
allowed, per standard of care (anastrazole or exemestane, not supplied by study).
Ribociclib will be supplied by Novartis. If patient has previously received letrozole,
anastrazole, and exemestane, (s)he is not eligible. For scenario 1, patients are
allowed to have started the aromatase inhibitor within 4 consecutive weeks prior to
protocol registration. For instance, it is acceptable for patient who will be treated
with letrozole in scenario #1, to have started letrozole within 4 consecutive weeks
prior to protocol registration. No prior fulvestrant allowed.
8. Scenario 2: the patient must have received an aromatase inhibitor (letrozole,
arimidex, exemestane) or tamoxifen or fulvestrant plus palbociclib as standard of care
or received a CDK4/6 inhibitor (palbociclib or ribociclib or abemaciclib), and
demonstrated evidence of disease progression. If the patient was enrolled in a
randomized clinical trial involving ribociclib or abemaciclib or palbociclib (such as
the MONALEESA or PALOMA series of trials), then it must be known after study
discontinuation and unblinding that the patient received the investigational drug and
not placebo. Ribociclib or abemaciclib or palbociclib can also be given as standard of
care. Documentation of progression and duration of response on aromatase inhibitor or
tamoxifen plus CDK 4/6 inhibitor should be provided whenever possible. If patient
received prior fulvestrant, exemestane must be the hormone therapy backbone in the
randomization. If patient received prior exemestane, fulvestrant must be the hormone
therapy backbone in the randomization. If neither has been administered, selection of
fulvestrant or exemestane in the randomization will be per investigator discretion.
9. Adequate baseline laboratory studies (hematologic and chemistry), including the
- Absolute neutrophil count ≥ 1500 per microliter, Platelets ≥ 75,000 per
microliter, Hemoglobin level ≥ 8.0 gm/dL on screening complete blood count.
- Potassium, sodium, total calcium (corrected only in the case of hypoalbuminemia),
magnesium, and phosphorus within normal limits of the local laboratory (screening
values can be rechecked after electrolyte repletion and before the first dose of
study medication, if necessary).
- Serum creatinine level ≤ 1.5 mg/dL or estimated glomerular filtration rate > 50
- In absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) should be below 2.5 × the upper limit of normal (ULN). If
the patient has liver metastases, ALT and AST should be < 5 × ULN.
- Total bilirubin ≤ 1.5 x ULN. (In patients with well documented Gilbert's
Syndrome, total bilirubin ≤ 3 × ULN with direct bilirubin within normal range.)
- international normalized ratio (INR) ≤ 1.5
10. a) Written informed consent and HIPAA authorization obtained from the subject/legal
representative prior to performing any protocol-related procedures b) Subjects must be
willing and able to comply with scheduled visits, treatment schedule, laboratory
testing, and other requirements of the study
11. Must be able to swallow ribociclib and oral aromatase inhibitor, such as letrozole or
1. Patient has a known hypersensitivity to any of the excipients of ribociclib, aromatase
inhibitors (such as letrozole) or fulvestrant
2. Active central nervous system (CNS) disease. History of CNS metastases or cord
compression is allowable if the patient has been clinically stable for at least 4
weeks since completion of definitive treatment and is off systemic steroids. In the
case of brain metastases, the patient must have stable or improved imaging at least 4
weeks after completion of definitive treatment. If there is evidence of active
leptomeningeal disease, the patient is ineligible.
3. Identified as having visceral crisis, lymphangitic spread, or leptomeningeal
carcinomatosis. Visceral crisis is not the mere presence of visceral metastases but
implies severe organ dysfunction as assessed by symptoms and signs, laboratory
studies, and rapid progression of the disease.
4. Received more than 1 prior systemic chemotherapy in the unresectable or metastatic
setting. If the patient received 1 prior systemic chemotherapy, the patient is
eligible. Having received prior therapies for breast cancer (such as everolimus or
experimental agents) does not affect eligibility for this study.
5. Completion of major surgery, chemotherapy, targeted therapy (such as everolimus or
experimental agents_ or radiation within 14 days prior to starting investigational
drug or has not recovered from major side effects. There is no required washout period
from completion of prior anti-estrogen therapy (either scenario) or prior CDK 4/6
inhibitor (if scenario 2) to initiation of ribociclib/placebo and anti-estrogen on
6. Residual acute toxic effects of prior anti-cancer therapy that have not resolved to
CTCAE v.4 Grade ≤1. Exception to this criterion: patients with grade 1 taxane-induced
neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a
safety risk for the patient as per investigator's discretion, are allowed to enter the
7. Presence of a concurrent malignancy or malignancy diagnosed within 5 years of
randomization, with the exception of basal or squamous cell carcinoma,
non-melanomatous skin cancer, curatively resected cervical cancer, localized prostate
cancer treated with curative intent, and stage I colorectal cancer treated with
8. 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
9. Patient has a known history of HIV infection (testing not mandatory).
10. Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality including any of the following:
- History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis,
or coronary artery bypass graft (CABG) within 6 months prior to study entry
- Documented cardiomyopathy
- Patient has a known Left Ventricular Fraction (LVEF) <50% as determined by
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
- Long QT syndrome or family history of long QT syndrome or family history of
idiopathic sudden death or congenital long QT syndrome, or any of the following:
i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia,
hypokalemia or hypomagnesaemia, history of cardiac failure, or history of
clinically significant/symptomatic bradycardia ii. Concomitant medications(s)
with a known risk to prolong the QT interval and/or known to cause Torsades de
Pointe that cannot be discontinued or replaced by safe alternative medication
(e.g. within 5 half-lives or 7 days prior to starting study drug) iii. Inability
to determine the QTc interval
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),
complete left bundle branch block, high-grade AV block (e.g., bifascicular block,
Mobitz type II and third degree AV block)
- Systolic Blood Pressure (SPB) >160 or <90 mmHg.
11. Corrected QT interval (QTcF) > 450 msec (QT interval using Fridericia's correction) on
screening electrocardiogram. If QTc prolongation is felt to be related to electrolyte
imbalance, an EKG can be repeated after correction of electrolytes. Mean resting heart
rate 50-100 bpm (determined from ECG).
12. The presence of any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator or treating physician's judgment, cause unacceptable safety
risks, contraindicate patient participation in the clinical study or compromise
compliance with the protocol. This includes uncontrolled infections that could
potentially be exacerbated by anti-neoplastic treatment, active untreated or
uncontrolled fungal bacterial or viral infections, etc.
13. Currently receiving treatment, including medications and herbal preparations, with
known strong inducers or inhibitors of cytochrome p450 enzymes CYP3A4/5 medications
that have a narrow therapeutic window and are predominately metabolized through
CYP3A4/5 or herbal preparations/medications, dietary supplements, which cannot be
discontinued prior to receiving investigational drug. Anti-retrovirals,
anti-microbials, and anti-arrhythmics are the most common medications that interact
with these enzyme. Please refer to Section 5: Pharmaceutical Information and Appendix
B for more information and a list of drugs that should not be used concurrently with
14. Patients who are receiving any other investigational agents concurrently or have
received investigational agents within 14 days or 5 half-lives of the compound or
active metabolites, whichever is longer before the first dose of the study treatment.
15 Patient is concurrently using hormone replacement therapy. 16. Subject is pregnant or
nursing. Serum or urine Beta-Human chorionic gonadotropin (HCG) must be checked in all pre-
and peri-menopausal patients. (Fulvestrant is pregnancy category D and CDK4/6 inhibitors
have demonstrated teratogenicity/fetotoxicity in animal studies.)