PRIMARY OBJECTIVES:
I. To estimate the safety and tolerability of the combination of ribociclib and an aromatase
inhibitor in adults age 70 or older with hormone receptor positive metastatic breast cancer.
SECONDARY OBJECTIVES:
I. To describe the full toxicity profile including all grades. II. To estimate the rate of
worst grades of myelosuppression (neutropenia, leukopenia, thrombocytopenia, and anemia),
neutropenic fever, gastrointestinal (GI) side effects (nausea, diarrhea, decreased appetite,
vomiting, stomatitis), fatigue, neuropathy, and thromboembolism.
III. To describe rates of dose reductions, dose holds, and hospitalizations. IV. To estimate
objective response rate and clinical benefit rate as defined by modified Response Evaluation
Criteria in Solid Tumors (RECIST) (1.1) criteria.
V. To estimate median progression-free and overall survival.
EXPLORATORY OBJECTIVES:
I. To estimate the rate of adherence to ribociclib. II. To explore factors other than
chronologic age that can affect toxicity rates as identified using a cancer-specific
geriatric assessment.
III. To describe the results of the Was It Worth It (WIWI) and the results of the Overall
Treatment Utility (OTU) Questionnaires.
OUTLINE:
Participants receive ribociclib orally (PO) once daily (QD) on days 1-21 and aromatase
inhibitor per treating investigator's discretion. Courses repeat every 28 days in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days, then annually
thereafter.
Inclusion Criteria:
- Patient has signed the informed consent (ICF) prior to any study procedures being
performed and is able to comply with protocol requirements
- Absolute neutrophil count ≥ 1.5 x 10^9 /L
- Platelets ≥ 100 x 10^9 /L
- Hemoglobin ≥ 9.0 g/dL
- 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
- Serum creatinine < 1.5 mg/dL or creatinine clearance ≥ 50 mL/min
- In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) < 2.5 x upper limit of normal (ULN); if the patient has liver
metastases, ALT and AST < 5 x ULN
- 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
- Patient with available standard 12-lead electrocardiogram (ECG) with the following
parameters at screening (defined as the mean of the triplicate ECGs):
- Fridericia's corrected QT (QTcF) interval at screening < 450msec (using
Fridericia's correction)
- Resting heart rate 50-90 beats per minute (bpm)
- Must be able to swallow ribociclib
- ≥ 70 years at time of enrollment; ≥ 70 to < 74 years, ≥ 75 years
- NOTE: A minimum of 20 participants must be ≥ 75 years; the remaining 20
participants may be ≥ 70 to < 74 years OR ≥ 75 years
- Life expectancy > 6 months
- Ability to read and comprehend in English (for completion of questionnaires)
- Clinical and histological confirmation of hormone receptor positive, HER2 receptor
negative metastatic breast cancer
- Measurable disease according to the Response Evaluation Criteria in Solid Tumors
(RECIST 1.1), or bone-only lytic or mixed lytic and blastic lesions that would be
accurately assessed by means of computed tomography (CT) or magnetic resonance imaging
(MRI)
- First or second line endocrine therapy for metastatic disease; one prior line of
chemotherapy for metastatic disease is allowed
- Resolution of all acute toxic effects of prior therapy or surgical procedures to
Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 1 (except alopecia)
prior to registration
Exclusion Criteria:
- Patient has a known hypersensitivity to any of the excipients of ribociclib
- Patient has a concurrent malignancy or malignancy within 3 years prior to starting
study drug, with the exception of adequately treated, basal or squamous cell
carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
- Patients with central nervous system (CNS) involvement unless they meet ALL 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
- 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)
- Patient has a known history of human immunodeficiency virus (HIV) infection (testing
not mandatory)
- 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, active untreated or uncontrolled
fungal, bacterial or viral infections, etc.)
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormalities, 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 6 months prior to screening
- History of documented congestive heart failure (New York Heart Association
functional classification III-IV)
- Documented cardiomyopathy
- Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia),
complete left bundle branch block, high-grade atrioventricular (AV) block (e.g.
bifascicular block, Mobitz type II and third-degree AV block)
- Long QT syndrome or family history of idiopathic sudden death or congenital long
QT syndrome, or any of the following:
- Risk factors for Torsades de pointe (TdP) including uncorrected hypokalemia
or hypomagnesemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia
- Concomitant use of medication(s) with a known risk to prolong the QT
interval and/or known to cause Torsades de pointe that cannot be
discontinued (within 5 half-lives or 7 days prior to starting study drug) or
replaced by safe alternative medication
- Inability to determine the QT interval on screening (QTcF, using
Fridericia's correction)
- Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening
- Patient is currently receiving any of the following medications and cannot be
discontinued 7 days prior to starting study drug:
- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
hybrids, pummelos, star-fruit, and Seville oranges
- That have a narrow therapeutic window and are predominantly metabolized through
CYP3A4/5
- Herbal preparations/medications, dietary supplements
- Patient is currently receiving or has received systemic corticosteroids ≤ 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)
- Patient is currently receiving warfarin or other coumadin-derived anticoagulant for
treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight
heparin (LMWH) or fondaparinux is allowed
- Participation in a prior investigational study within 30 days prior to enrollment or
within 5 half-lives of the investigational product, whichever is longer
- Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for
palliation ≤ 2 weeks prior to starting study drug, and 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 (Ellis, 1961) was irradiated
- 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)
- Patient has not recovered from all toxicities related to prior anticancer therapies to
National Cancer Institute (NCI)-CTCAE version 4.03 grade < 1 (exception to this
criterion: patients with any grade of alopecia are allowed to enter the study)
- Patient with a Child-Pugh score B or C
- Patient has a history of non-compliance to medical regimen or inability to grant
consent
- Sexually active males unless they use a condom during intercourse while taking the
drug and for 21 days after stopping treatment and should not father a child in this
period; a condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid