Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-based Cohorts

Exclusion Criteria

• •Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's judgment.
• •Patient currently prescribed a CDK4/6 inhibitor (e.g., ribociclib, abemaciclib, or palbociclib).
• •Patients with central nervous system (CNS) symptomatic or untreated metastases
• •History of liver transplant or allogeneic bone marrow transplantation
• •Patient with a known hypersensitivity to any of the excipients of ribociclib (e.g. ribociclib tablets coating contains soya lecithin, and therefore should not be taken by patients who are allergic to peanuts or soya) or of fulvestrant.
• •Patient is concurrently using other anti-cancer therapy besides those in the study protocol (e.g., letrozole, fulvestrant, goserelin, leuprolide). Any other prior neo-/adjuvant anti-cancer therapy must be stopped at least 5 half-lives or 7 days, whichever is longer, before the date of ribociclib initiation.
• •Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major toxicities
• •Patient has not recovered from acute clinical and laboratory toxicities related to prior anticancer therapies to NCI CTCAE v5.0 grade ≤ 1 (except for alopecia, neuropathy, and amenorrhea or other toxicities not considered a safety risk for the patient at investigator's discretion).
• •Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to ribociclib initiation and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
• •Patient has a concurrent malignancy, with the exception of adequately treated basal or squamous cell skin carcinoma, stage 1 melanoma, or curatively resected cervical carcinoma in situ. Patients may still enroll with a concurrent malignancy after receiving approval from the study PI.
• •Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug (e.g., uncontrolled 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 to the patient, contraindicate patient participation in the clinical study, or compromise compliance with the protocol.
• •Patient has clinically significant, uncontrolled heart disease or who are at significant risk of developing QT prolongation, including any of the following:
• •1. Documented myocardial infarction (MI), angina pectoris, coronary artery intervention, or pericarditis within 6 months prior to study entry
• •2. Documented cardiomyopathy, congestive heart failure, valvular heart disease, congenital heart disease, or prior cardiac surgery
• •3. Left Ventricular Ejection Fraction (LVEF) \< 50% (testing is not mandatory)
• •4. Personal diagnosis of long QT syndrome, cardiac channelopathies, family history of idiopathic sudden death, congenital long QT syndrome or channelopathies
• •5. Personal risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia, hypomagnesemia, or need for concomitant medications with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug, whichever is longer)
• •6. Clinically significant cardiac arrhythmias or conduction abnormalities, including, but not limited to ventricular tachycardia, atrial tachyarrhythmia, left bundle branch block, right bundle branch block, QRS prolongation (greater than 120 ms), intraventricular conduction delay, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
• •7. Uncontrolled hypertension
• •8. Inability to determine the QTc interval
• •Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1:
• •1. Concomitant medications, herbal supplements, and/or fruits that are strong inducers or inhibitors of CYP3A4/5.
• •2. Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
• •3. Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to induction of CYP3A enzymes, thereby potentially reducing ribociclib drug exposure to sub-therapeutic levels. Systemic corticosteroid treatment should not be given during the study treatment with ribociclib, except for:
• •* Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular)
• •* A short duration (\< 5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency of 4 mg dexamethasone (e.g. for chronic obstructive pulmonary disease or as an antiemetic).
• •* Medications that prolong the QTc interval.
• •Inability to comply with study requirements.
• •Psychiatric illness or social situation that would limit compliance with study requirements.
• •Patients with clinically significant liver disease, including active viral or other known hepatitis, current alcohol abuse, or cirrhosis.
• •Known active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\]) or known active hepatitis C (defined as a positive test for hepatitis C viral load by polymerase chain reaction \[PCR\]).
• •* Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen \[anti-HBc\] antibody test) are eligible.