Ribociclib and Aromatase Inhibitor in Treating Older Participants With Hormone Receptor Positive Metastatic Breast Cancer

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