Ribociclib and Aromatase Inhibitor in Treating Older Participants With Hormone Receptor Positive Metastatic Breast Cancer
Ribociclib and Aromatase Inhibitor in Treating Older Participants With Hormone Receptor Positive Metastatic Breast Cancer
This phase IIA trial studies the side effects of ribociclib and aromatase inhibitor and how
 well they work in treating participants with hormone receptor positive breast cancer that has
 spread to other places in the body. Ribociclib and aromatase inhibitors may stop the growth
 of tumor cells by blocking some of the enzymes needed for cell growth.
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

 -  Must be able to swallow ribociclib

 -  Age: >= 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

 -  Subjects must be able to communicate with the investigator and comply with the
 requirements of the study procedures

 -  Patient has a histologically and/or cytologically confirmed diagnosis of
 estrogen-receptor positive and/or progesterone receptor positive breast cancer,
 HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC
 status of 0, 1+ or 2+, and metastatic breast cancer

 -  First or second line endocrine therapy for metastatic disease. One prior line of
 chemotherapy for metastatic disease is allowed

 -  Absolute neutrophil count >= 1.5 x 10^9 /L, at screening

 -  Platelets >= 100 x 10^9 /L, at screening

 -  Hemoglobin >= 9.0 g/dL, at screening

 -  Patient must have the following laboratory values within normal limits or corrected to
 within normal limits with supplement before the first dose of study medication:

 -  Sodium

 -  Potassium

 -  Magnesium

 -  Total calcium (corrected for serum albumin)

 -  Phosphorous

 -  Serum creatinine < 1.5 mg/dL or creatinine clearance >= 50 mL/min, at screening

 -  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, at screening

 -  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, at screening

 -  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)

 Exclusion Criteria:

 -  Patient received prior treatment with any CDK4/6 inhibitor

 -  Patient has a known hypersensitivity to any of the excipients of ribociclib

 -  Patients with a prior malignancy diagnosed within 2 years AND with evidence of disease
 (except adequately treated, basal or squamous cell carcinoma, non-melanomatous skin
 cancer or curatively resected cervical cancer)

 -  Patient with concurrent malignancy that is not clinically stable AND needs
 tumor-directed therapy

 -  Patients with central nervous system (CNS) involvement unless they meet ALL the
 following criteria:

 -  Untreated brain metastases (e.g., lesions < 1cm) not needing immediate local
 therapy

 -  Previously treated brain metastases not needing immediate local therapy

 -  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

 -  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

 -  Documented cardiomyopathy

 -  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).

 -  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

 -  Warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or
 otherwise. Therapy with heparin, low molecular weight heparin (LMWH), newer
 anticoagulation agents such as direct factor Xa inhibitors, or fondaparinux is
 allowed

 -  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 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 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.)

 -  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 has had major surgery and/or radiotherapy 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 with a Child-Pugh score B or C

 -  Patient has not recovered from the acute effects of prior systemic therapy (until the
 toxicity resolves to either baseline or at least grade 1) except for residual alopecia
 or peripheral neuropathy

 -  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