Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer.

Advanced Breast Cancer Clinical Trial

— MONALEESA-3  

Official title:

A Randomized Double-blind, Placebo-controlled Study of Ribociclib in Combination With Fulvestrant for the Treatment of Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer Who Have Received no or Only One Line of Prior Endocrine Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02422615
• Other study ID #: CLEE011F2301
• Secondary ID: 2015-000617-43
• Status: Completed
• Phase: Phase 3
• Start date: June 9, 2015
• Est. completion date: January 11, 2023

Study information

• Verified date: November 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main aim of this study was to evaluate the efficacy and safety of adding ribociclib to fulvestrant in men and postmenopausal women with hormone receptor positive (HR+), HER2-negative advanced breast cancer.

Description:

This study was a randomized, phase III, double-blind, placebo-controlled international trial aimed at determining the efficacy and safety of treatment with fulvestrant in combination with ribociclib compared to fulvestrant with placebo in men and postmenopausal women diagnosed with HR+, HER2-negative advanced breast cancer. The study comprised four phases: screening (up to 28 days), randomized treatment, post-treatment disease progression follow-up, and post-treatment survival follow-up. Enrolled participants were randomly assigned to receive either fulvestrant+ribociclib or fulvestrant+placebo in a ratio of 2:1. The randomization process was stratified based on the presence of liver and/or lung metastases (yes versus no) and prior endocrine therapy. Treatment was administered until disease progression, occurrence of unacceptable toxicity, or discontinuation from the study treatment for other reasons. Participants who discontinued treatment due to reasons other than disease progression or withdrawal of consent for efficacy follow-up continued to be monitored until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision. All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached. A protocol amendment 4 (dated 29-Jan-2020) allowed for unblinding of study participants, and those still receiving placebo had the option to switch to the ribociclib arm. The decision for crossover was made at the investigator's discretion and required patient consent.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 726
• Est. completion date: January 11, 2023
• Est. primary completion date: November 3, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

1. Patients were adults, both male and female, aged = 18 years at the time of providing informed consent. Female patients were required to be postmenopausal. Informed consent was obtained prior to any trial-related activities, following local guidelines.

2. Patients had a confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer, determined through histological and/or cytological examination by a local laboratory. Patients also had HER2-negative breast cancer.

3. Patients had either measurable disease as per RECIST 1.1 criteria or at least one predominantly lytic bone lesion.

4. Patients had advanced breast cancer, which included locoregionally recurrent disease not amenable to curative therapies (such as surgery or radiotherapy) or metastatic

breast cancer. Patients fell into one of the following categories:

• Newly diagnosed with advanced/metastatic breast cancer and treatment-naïve.
• Relapsed with documented evidence of relapse more than 12 months after completing (neo)adjuvant endocrine therapy, without any prior treatment for advanced/metastatic disease.
• Relapsed with documented evidence of relapse on or within 12 months from completing (neo)adjuvant endocrine therapy, without any prior treatment for advanced/metastatic disease.
• Relapsed with documented evidence of relapse more than 12 months after completing adjuvant endocrine therapy and subsequently progressed after receiving one line of endocrine therapy (antiestrogen or aromatase inhibitor) for advanced/metastatic disease.
• Newly diagnosed with advanced/metastatic breast cancer at diagnosis and progressed after receiving one line of endocrine therapy (antiestrogen or aromatase inhibitor), with documented evidence of progression.

5. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Patients had adequate bone marrow and organ function. Key Exclusion Criteria: Patients with symptomatic visceral disease or disease burden that rendered them ineligible for endocrine therapy, based on the investigator's judgment.

2. Patients who had received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, or any CDK4/6 inhibitor.

3. Patients with inflammatory breast cancer at the screening stage. 4. Patients with central nervous system (CNS) involvement, unless they were at least 4 weeks from completing prior therapy before initiating the study treatment and had a stable CNS tumor at the time of screening. They were also required not to be receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases.

5. Patients with clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.

6. Patients who were currently receiving any of the following substances, which could not

be discontinued 7 days prior to initiating treatment:

• Known strong inducers or inhibitors of CYP3A4/5.
• Substances with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
• Substances with a narrow therapeutic window and predominantly metabolized through CYP3A4/5.
• Herbal preparations/medications, dietary supplements.

Related Conditions & MeSH terms

• Advanced Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Ribociclib
Ribociclib capsules were administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle.
• Fulvestrant
Fulvestrant was administered via intramuscular injections at a dose of 500mg every 28 days, starting on Day 1 of each cycle. In Cycle 1, an additional dose of Fulvestrant was given on Day 15.
• Placebo
Placebo capsules were administered orally for 21 consecutive days within a 28-day cycle.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	East Melbourne	Victoria
Australia	Novartis Investigative Site	Herston	Queensland
Australia	Novartis Investigative Site	Nedlands	Western Australia
Australia	Novartis Investigative Site	St Leonards	New South Wales
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Vienna
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Aalst
Belgium	Novartis Investigative Site	Charleroi
Belgium	Novartis Investigative Site	Hasselt
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Namur
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Canada	Novartis Investigative Site	Brampton	Ontario
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	Kingston	Ontario
Canada	Novartis Investigative Site	Moncton	New Brunswick
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Newmarket	Ontario
Canada	Novartis Investigative Site	Rimouski	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Surrey	British Columbia
Canada	Novartis Investigative Site	Trois Rivieres	Quebec
Canada	Novartis Investigative Site	Vancouver	British Columbia
Canada	Novartis Investigative Site	Victoria	British Columbia
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Monteria
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Brno Bohunice	Czech Republic
Czechia	Novartis Investigative Site	Liberec	Czech Republic
Czechia	Novartis Investigative Site	Prague 8
Czechia	Novartis Investigative Site	Praha
Denmark	Novartis Investigative Site	Aalborg
Denmark	Novartis Investigative Site	Aarhus
Denmark	Novartis Investigative Site	Copenhagen
Denmark	Novartis Investigative Site	Herlev
Denmark	Novartis Investigative Site	Odense C
Denmark	Novartis Investigative Site	Vejle
France	Novartis Investigative Site	Besancon Cedex
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Brest
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Le Mans Cedex
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Limoges
France	Novartis Investigative Site	Paris 13
France	Novartis Investigative Site	Pierre Benite
France	Novartis Investigative Site	Reims	Marne
France	Novartis Investigative Site	Saint-Cloud	Hauts De Seine
France	Novartis Investigative Site	Strasbourg	Cedex
France	Novartis Investigative Site	Toulon La Seyne Sur Mer
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bielefeld
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Fuerth
Germany	Novartis Investigative Site	Georgsmarienhuette	Lower Saxony
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Langen	Hessen
Germany	Novartis Investigative Site	Luebeck
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Mühlhausen
Germany	Novartis Investigative Site	Oldenburg
Germany	Novartis Investigative Site	Ravensburg
Germany	Novartis Investigative Site	Saarbruecken
Germany	Novartis Investigative Site	Troisdorf
Germany	Novartis Investigative Site	Tuebingen
Germany	Novartis Investigative Site	Velbert
Germany	Novartis Investigative Site	Weiden
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szolnok
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	L'Aquila	AQ
Italy	Novartis Investigative Site	Lecce	LE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Pontedera	PI
Italy	Novartis Investigative Site	Rozzano	MI
Jordan	Novartis Investigative Site	Amman
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Malaysia	Novartis Investigative Site	Johor Bahru	Johor
Malaysia	Novartis Investigative Site	Kuching	Sarawak
Mexico	Novartis Investigative Site	Oaxaca
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Deventer
Netherlands	Novartis Investigative Site	Enschede
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Hoofddorp
Netherlands	Novartis Investigative Site	Maastricht
Netherlands	Novartis Investigative Site	Nieuwegein
Netherlands	Novartis Investigative Site	Roermond
Netherlands	Novartis Investigative Site	Sittard-Geleen
Netherlands	Novartis Investigative Site	Tilburg
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Konin
Poland	Novartis Investigative Site	Warszawa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Arkhangelsk
Russian Federation	Novartis Investigative Site	Tambov
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	A Coruna	Galicia
Spain	Novartis Investigative Site	Alcorcon	Madrid
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Granada	Andalucia
Spain	Novartis Investigative Site	Madrid	Andalucia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	San Sebastian de los Reyes	Madrid
Spain	Novartis Investigative Site	Sant Joan Despi	Barcelona
Spain	Novartis Investigative Site	Sevilla	Andalucia
Sweden	Novartis Investigative Site	Eskilstuna
Sweden	Novartis Investigative Site	Sundsvall
Sweden	Novartis Investigative Site	Vaxjo
Switzerland	Novartis Investigative Site	Aarau
Switzerland	Novartis Investigative Site	Basel
Switzerland	Novartis Investigative Site	Zuerich
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	Newcastle Upon Tyne
United Kingdom	Novartis Investigative Site	Plymouth	Devon
United States	University of New Mexico Cancer Center SC	Albuquerque	New Mexico
United States	Ironwood Cancer and Research Centers SC-2	Chandler	Arizona
United States	Florida Cancer Research Institute Dept of Oncology	Davie	Florida
United States	Providence Regional Cancer Partnership .	Everett	Washington
United States	Highlands Oncology Group .	Fayetteville	Arkansas
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	CR Wood Cancer Center SC	Glens Falls	New York
United States	Penn State University Milton S Hershey Medical Center SC	Hershey	Pennsylvania
United States	Moanalua Medical Center. Attn: Oncology Dept SC	Honolulu	Hawaii
United States	Millennium Research Clin Develop SC	Houston	Texas
United States	Jackson Oncology Associates SC	Jackson	Mississippi
United States	Providence Regional Cancer System SC	Lacey	Washington
United States	Clinical Research Alliance .	Lake Success	New York
United States	UCLA Medical Center .	Los Angeles	California
United States	Southern Cancer Center PC SC-2	Mobile	Alabama
United States	Meridian Health Systems Regulatory	Neptune	New Jersey
United States	NYU Langone Med Center CV Research NYU Langone Medical Center	New York	New York
United States	Northern Utah Cancer Associates CFTY720DUS01	Ogden	Utah
United States	Florida Hospital Cancer Institute SC	Orlando	Florida
United States	UF Health Cancer Center at Orlando Health	Orlando	Florida
United States	Oncology Specialists, SC Advocate Medical Group-Niles	Park Ridge	Illinois
United States	Central Coast Medical Oncology Corporation SC	Santa Maria	California
United States	St Joseph Heritage Healthcare	Santa Rosa	California
United States	Virginia Mason Medical Center-Oncology SC	Seattle	Washington
United States	John D Archbold Memorial Hospital Main	Thomasville	Georgia
United States	Genesis Cancer Services SC	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Bulgaria,  Canada,  Colombia,  Czechia,  Denmark,  France,  Germany,  Hungary,  Italy,  Jordan,  Korea, Republic of,  Lebanon,  Malaysia,  Mexico,  Netherlands,  Norway,  Poland,  Portugal,  Russian Federation,  Singapore,  Spain,  Sweden,  Switzerland,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) Per Investigator Assessment	PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression.; PFS was assessed via local radiology assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group.; The distribution of PFS between the two arms was compared using a stratified log-rank test at a one-sided 2.5% level of significance. The PFS hazard ratio with two-sided 95% confidence interval was derived from the stratified Cox proportional hazards model.	From randomization to first documented progression or death, assessed up to approximately 26 months
Secondary	Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death from any cause. In cases where the patient's death was not recorded, the OS value was censored at the date of the last known patient's survival status. As per protocol, the final OS analysis was conducted after approximately 351 deaths were documented.; OS was estimated using the Kaplan-Meier method. The median OS, along with 95% confidence intervals (CIs), was reported for each treatment group.; The distribution of OS between the two treatment arms was compared using a log-rank test at one-sided cumulative 2.5% level of significance. A stratified Cox regression was used to estimate the OS hazard ratio and the associated 95% CI.	From randomization to death, assessed up to approximately 46 months
Secondary	Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC)	PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression.; PFS was assessed via BIRC assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group.	From randomization to first documented progression or death, assessed up to approximately 26 months
Secondary	Overall Response Rate (ORR) Per Investigator Assessment	ORR was defined as the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per investigator assessment.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to approximately 26 months
Secondary	Clinical Benefit Rate (CBR) Per Investigator Assessment	CBR was defined as the percentage of participants with a best overall response of CR or PR or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 as per investigator assessment.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.; SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.	Up to approximately 26 months
Secondary	Time to Response (TTR) Per Investigator Assessment	TTR was defined as the time from randomization to the first documented and confirmed response (CR or PR) as defined by RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate TTR, and the median TTR, along with 95% confidence intervals, was reported for each treatment group. Participants who did not achieve a confirmed response were censored at the maximum follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause) or at the date of last adequate tumor assessment otherwise.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	From randomization to first response, assessed up to approximately 26 months
Secondary	Duration of Response (DOR) Per Investigator Assessment	DOR was defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate DOR, and the median DOR, along with 95% confidence intervals, was reported for each treatment group. If a participant had not had an event, duration was censored at the date of last adequate tumor assessment.; CR: Disappearance of all lesions with lymph nodes measuring < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	From first documented response to progression or death, assessed up to approximately 26 months
Secondary	Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in One Score Category	ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration was defined as the time from the date of randomization to the date of the event, defined as experiencing an increase in ECOG PS by at least one category from the baseline or death. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive deterioration, along with 95% confidence intervals, was reported for each treatment group. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment.	Up to approximately 26 months
Secondary	Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)	The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.; The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive 10% deterioration, along with 95% confidence intervals, was reported for each treatment group. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation.	Up to approximately 26 months
Secondary	Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30	The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.; The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicates improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits occurred every 8 weeks during the initial 18 months since start of treatment, followed by visits every 12 weeks until disease progression.	Baseline, every 8 weeks after randomization during 18 months, then every 12 weeks up to end of treatment; end of treatment; and every 8 or 12 weeks post-treatment until progression (post-treatment efficacy visits), assessed up to approximately 26 months
Secondary	Ribociclib Plasma Concentrations	Blood samples were collected to assess the concentration by time point for ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption.	Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle=28 days
Secondary	LEQ803 Plasma Concentrations	Blood samples were collected to assess the concentration by time point for LEQ803, a metabolite of ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption.	Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle = 28 days