| Eligibility |
Inclusion Criteria:
- Signed informed consent must be obtained prior to any screening procedures.
- Female =18 years old at the time of informed consent
- Those who self-identify as African American or Black are eligible for that respective
cohort
- Those who self-identify as non-Hispanic White are eligible for that respective cohort
- Postmenopausal or premenopausal. Patient has a known menopausal status at the time of
the informed consent form signature. The patient is considered postmenopausal if: i)
she has had prior bilateral oophorectomy; ii) is age = 60 years; iii) is age <60 years
and has had amenorrhea for 12 or more months (in the absence of chemotherapy,
tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH)
and estradiol in the postmenopausal range per local normal ranges. All other patients
who do not meet the criteria for postmenopausal status are considered premenopausal
and will receive goserelin or leuprolide for ovarian suppression
- Each race-based cohort has a predetermined number of patients with each CYP3A5
phenotype per the sample size calculation (section 9.1). Patients will be screen for
CYP3A5: - African American or Black (At least 3 participants who are CYP3A5 poor
metabolizers, No more than 15 participants who are CYP3A5 intermediate or normal
metabolizers); - Non-Hispanic White (At least 3 participants who are CYP3A5
intermediate or normal metabolizers, No more than 15 participants who are CYP3A5 poor
metabolizers)
- Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not
amenable to curative therapy
- Treated, stable and asymptomatic brain metastases are permitted
- ECOG performance status 0-3
- Documentation of estrogen receptor (ER) positive and/or progesterone receptor (PR)
positive tumor (=1% positive stained cells) based on most recent tumor biopsy (discuss
with the Principal Investigator if results in different biopsies are discordant in
terms of hormone receptor positivity) utilizing an assay consistent with local
standards.
- Documented HER2-negative tumor based on local testing on most recent tumor biopsy:
HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by in
situ hybridization (FISH/CISH/SISH) defined by current ASCO/CAP (American Society of
Clinical Oncology/College of American Pathologists) guidelines. Patients with
equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines
are eligible, as long as they have not received and are not scheduled to receive
anti-HER2 treatment.
- Must be capable of understanding and complying with parameters as outlined in the
protocol and able to sign and date the informed consent, approved by the IRB, prior to
the initiation of any screening or study-specific procedures.
- Patient must be able to swallow ribociclib tablets.
- Patient must be able to communicate with the investigator and comply with the
requirements of the study procedures.
- Patient has adequate bone marrow and organ function as defined by the following
laboratory values:
1. Absolute neutrophil count (ANC) = 1,200/mm; Patients must be able to meet the
criteria without receipt of colony stimulating factors within 2 weeks before
obtaining sample
2. Platelets = 100,000/mm3; Patients must be able to meet the criteria without
receipt of transfusion within 2 weeks before obtaining sample
3. Hemoglobin = 8 g/dL; Patients must be able to meet the criteria without receipt
of transfusion within 2 weeks before obtaining sample
4. Estimated glomerular filtration rate (eGFR) = 30 mL/min/1.73m2 according to the
CKD EPI equation
5. Total bilirubin < ULN except for patients with Gilbert's syndrome who may only be
included if the total bilirubin is = 3.0 × ULN or direct bilirubin = 1.5 × ULN.
6. Aspartate transaminase (AST) < 2.5 × ULN, except for patients with liver
metastases, who are only included if the AST is <5 × ULN.
7. Alanine transaminase (ALT) < 2.5 × ULN, except for patients with liver
metastases, who are only included if the ALT is < 5 × ULN.
8. Alkaline phosphatase =2.5 x ULN (=5.0 x ULN if bone metastases present)
- Patient must have the following laboratory values within normal limits or corrected to
within normal limits with supplements, or are not clinically significant per the
Investigator
1. Sodium
2. Potassium
3. Calcium
- The following tests are not necessary. However, if results are available, values
should be as follows:
- INR = 1.5 (unless the patient is receiving anticoagulants and the INR is within
the therapeutic range of intended use for that anticoagulant within 7 days prior
to the first dose of study drug).
- Magnesium within normal limits or corrected to within normal limits with
supplements, or is not clinically significant per the Investigator.
- Standard 12-lead electrocardiogram values defined as (obtained from baseline
electrocardiogram):
1. QTc interval at screening < 450 ms (using Fridericia's correction)
2. Mean resting heart rate >= 50 bpm (determined from the electrocardiogram)
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.
- Patients with positive hepatitis C antibody AND negative quantitative hepatitis C
by PCR AND no clinical/laboratory evidence of cirrhosis are eligible. Patients
who have completed curative therapy for HCV are eligible if they meet all other
parameters for enrollment.
- Patients are not required to undergo testing for HBV or HCV for enrollment
- Known uncontrolled HIV infection defined as any of the following 3 criteria:
- CD4 counts = 350 cells/µL; or
- Serum HIV viral load = 400 copies/mL; or
- Have been taking an antiretroviral regimen for < 4 weeks prior to treatment with
study drugs if anti-retroviral therapy is deemed necessary or appropriate by the
investigator.
- Patients are not required to undergo testing for HIV for enrollment.
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