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Breast CancerPhase 4LEANORANCT04657679

Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-based Cohorts

A Phase 4 study testing Ribociclib in people with Breast Cancer, run by Georgetown University at 3 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The aim is to determine the pharmacological and biochemical association between ribociclib exposure and CYP3A variants in African American/Blacks and Non-Hispanic White patients. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Cancer
What is being tested?
Ribociclib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
21 participants
Where
3 sitesUnited States
Study dates
20 May 2021to 30 Oct 2023
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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:
  • 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
  • Platelets ≥ 100,000/mm3; Patients must be able to meet the criteria without receipt of transfusion within 2 weeks before obtaining sample
  • Hemoglobin ≥ 8 g/dL; Patients must be able to meet the criteria without receipt of transfusion within 2 weeks before obtaining sample
  • Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 according to the CKD EPI equation
  • 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.
  • Aspartate transaminase (AST) < 2.5 × ULN, except for patients with liver metastases, who are only included if the AST is <5 × ULN.
  • Alanine transaminase (ALT) < 2.5 × ULN, except for patients with liver metastases, who are only included if the ALT is < 5 × ULN.
  • 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
  • Sodium
  • Potassium
  • 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):
  • QTc interval at screening < 450 ms (using Fridericia's correction)
  • Mean resting heart rate >= 50 bpm (determined from the electrocardiogram)

Who cannot join

  • 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.
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  • 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:
  • Documented myocardial infarction (MI), angina pectoris, coronary artery intervention, or pericarditis within 6 months prior to study entry
  • Documented cardiomyopathy, congestive heart failure, valvular heart disease, congenital heart disease, or prior cardiac surgery
  • Left Ventricular Ejection Fraction (LVEF) < 50% (testing is not mandatory)
  • Personal diagnosis of long QT syndrome, cardiac channelopathies, family history of idiopathic sudden death, congenital long QT syndrome or channelopathies
  • 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)
  • 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)
  • Uncontrolled hypertension
  • 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:
  • Concomitant medications, herbal supplements, and/or fruits that are strong inducers or inhibitors of CYP3A4/5.
  • Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
  • 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.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Tufts Medical Center

    Boston, Massachusetts, 02111

  • MedStar Georgetown University Hospital

    Washington D.C., District of Columbia, 20007

  • Medstar Washington Hospital Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

Official title: evaLuation of Variations pharmacokinEtics and phArmacogeNOmics of Ribociclib in rAce-based Cohorts: The LEANORA Study

The aim is to determine the pharmacological and biochemical association between ribociclib exposure and CYP3A variants in African American/Blacks and Non-Hispanic White patients. The investigators hypothesize that patients treated with ribociclib who are CYP3A5 poor metabolizers may be exposed to higher levels of ribociclib than CYP3A5 intermediate or normal metabolizers. The findings could allow clinicians to tailor treatments to maintain therapeutic doses while limiting toxicities.

Read the detailed description

This prospective, multicenter, cohort study will assess ribociclib (600 mg PO daily) pharmacokinetics and pharmacogenomics in female patients with HR+/HER2- metastatic breast cancer. This design will be used for two independent, race-based cohorts: 18 African American/Black patients and 18 Non-Hispanic White patients. Women are eligible if they are older than 18, have HR+/HER2- mBC and are candidates for treatment with a CDK 4/6 inhibitor and endocrine therapy. Patients are ineligible if currently prescribed a medication that inhibits or induces the CYP3A isoenzymes, have baseline electrocardiogram abnormalities, or are otherwise considered to be ineligible for ribociclib. Participants will provide serial blood samples during the first cycle (collected immediately prior to the ribociclib dose, and 0.5hr ± 5min, 1hr ± 5min, 2hr ± 15min, 4hr ± 15min, 6hr ± 15min after the daily dose of ribociclib). Plasma samples will be analyzed via mass spectrometry to characterize the pharmacokinetics (e.g., AUC0-24, Cmax). Pharmacogenetic testing will be performed using the PharmacoScanTM microarray, which tests 4,627 markers in 1,191 genes, including variants in CYP3A4 and CYP3A5.

Conditions
Breast Cancer
Being tested
Ribociclib
Keywords
HR-positive/HER2-negative metastatic breast cancer
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RibociclibDrug

    Also called KISQALI

    Patients will receive ribociclib 600 mg oral (PO) daily for 21 consecutive days of 28-day cycles and endocrine therapy with either letrozole or fulvestrant. Fulvestrant 500 mg intramuscular (IM) will be administered on days 1, 15, 29 of cycle one, and then monthly. Letrozole 2.5 mg oral daily continuously. If premenopausal women have not undergone bilateral salpingo- oophorectomy, they will receive a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin leuprolide) for ovarian suppression in combination with fulvestrant or letrozole and ribociclib.

Study groups in NCT04657679
Study groupRoleWhat they receive
African American/BlackActive comparatorSubject who self identify as African American or Black with metastatic HR+/HER2- advanced breast cancer (estimate 3 participants who are CYP3A5 poor metabolizers and approximately 15 participants who are CYP3A5 intermediate or normal metabolizers)
Receives: Drug: Ribociclib
Non-Hispanic WhiteActive comparatorSubjects who self-identify as non-Hispanic White with metastatic HR+/HER2- advanced breast cancer (estimate 3 participants who are CYP3A5 poor metabolizers and approximately 15 participants who are CYP3A5 intermediate or normal metabolizers)
Receives: Drug: Ribociclib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Ribociclib Area-under-the-curve (AUC)

    Compare the exposure (i.e., AUC) of ribociclib at steady-state between CYP3A5 poor metabolizers (PM) and CYP3A5 intermediate or normal metabolizers (IM/NM) in each independent race-based cohort of women with advance breast cancer

    Measured: On day 8-16 of cycle 1 (each cycle is 28 days)

Secondary outcomes (9)

  1. Ribociclib Pharmacokinetic Properties - Maximum Concentration (Cmax)

    Maximum concentration (Cmax) at steady state between different CYP3A5 phenotypes

    Measured: On day 8-16 of cycle 1 (each cycle is 28 days)

  2. Ribociclib Pharmacokinetic Properties - the Time to Reach Cmax (Tmax)

    the time to reach Cmax (Tmax) at steady state between different CYP3A5 phenotypes

    Measured: On day 8-16 of cycle 1 (each cycle is 28 days)

  3. Ribociclib Pharmacokinetic Properties - Clearance

    clearance at steady state between different CYP3A5 phenotypes

    Measured: On day 8-16 of cycle 1 (each cycle is 28 days)

  4. Ribociclib Pharmacokinetic Properties - Volume of Distribution(vd)

    Volume of distribution(vd) at steady state between different CYP3A5 phenotypes

    Measured: days 8-16 of cycle 1 (28 day cycle)

  5. Ribociclib Pharmacokinetic Properties - Elimination Half-life

    Elimination half-life (t1/2) at steady state between different CYP3A5 phenotypes

    Measured: On day 8-16 of cycle 1 (each cycle is 28 days)

  6. Change in QTc Interval

    Change in QTc interval between 1) baseline and between days 8-16 of cycle 1 (midcycle), and 2) baseline and scheduled visit prior to initiation of cycle 2 (C2), between different CYP3A5 phenotypes.

    Measured: Baseline, day 8-16 of cycle 1 and prior to cycle 2 (each cycle is 28 days)

  7. Laboratory Abnormalities - Neutropenia

    Occurrence of neutropenia

    Measured: from baseilne through prior to cycle 2 (each cycle is 28 days)

  8. Laboratory Abnormalities - Aspartate Aminotransferase (AST)

    Occurrence of Laboratory abnormalities: AST

    Measured: From Baseline through prior to cycle 2 (each cycle is 28 days)

  9. Laboratory Abnormalities -Alanine Aminotransferase (ALT)

    Occurrence of Laboratory abnormalities: ALT between between different CYP3A5 phenotypes.

    Measured: From Baseline to prior to cycle 2 (each cycle is 28 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Dec 2020
  2. Study start20 May 2021
  3. Primary completion30 Oct 2023
  4. Study completion30 Oct 2023

Why it stopped: Sufficient accrual into the African American/Black patient cohort and insufficient accrual into the NHW patient cohort.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
21 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04657679
Sponsor's protocol ID
STUDY00003100
Acronym
LEANORA
Status last verified
Sep 2024
First submitted
20 Nov 2020
Last updated
26 Nov 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Ribociclib in people with Breast Cancer, run by Georgetown University at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 33 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 26 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Nov 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Ribociclib Area-under-the-curve (AUC) (time frame: On day 8-16 of cycle 1 (each cycle is 28 days)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04657679.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Nov 2024.

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