Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer. (MONALEESA-3)

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: Ribociclib; Drug: Fulvestrant; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 726
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • St Leonards, New South Wales, Australia, 2065
      • Novartis Investigative Site
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Novartis Investigative Site
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Vienna, Austria, A-1100
    • Novartis Investigative Site
  • Wien, Austria, A-1090
    • Novartis Investigative Site
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Novartis Investigative Site
• Belgium
  • Aalst, Belgium, 9300
    • Novartis Investigative Site
  • Charleroi, Belgium, 6000
    • Novartis Investigative Site
  • Hasselt, Belgium, 3500
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
  • Namur, Belgium, 5000
    • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1756
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1606
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1303
    • Novartis Investigative Site
• Canada
  • British Columbia
    • Surrey, British Columbia, Canada, V3V 1Z2
      • Novartis Investigative Site
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Novartis Investigative Site
    • Victoria, British Columbia, Canada, V8R 6V5
      • Novartis Investigative Site
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 8X3
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Novartis Investigative Site
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • Novartis Investigative Site
    • Kingston, Ontario, Canada, K7L 5P9
      • Novartis Investigative Site
    • Newmarket, Ontario, Canada, J7Y 2P9
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3G 1L5
      • Novartis Investigative Site
    • Rimouski, Quebec, Canada, G5L 5T1
      • Novartis Investigative Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Novartis Investigative Site
    • Trois Rivieres, Quebec, Canada, G8Z 3R9
      • Novartis Investigative Site
• Colombia
  • Bogota, Colombia, 110221
    • Novartis Investigative Site
  • Monteria, Colombia, 230004
    • Novartis Investigative Site
• Czechia
  • Brno, Czechia, 65653
    • Novartis Investigative Site
  • Prague 8, Czechia, 180 81
    • Novartis Investigative Site
  • Praha, Czechia, 12808
    • Novartis Investigative Site
  • Czech Republic
    • Brno Bohunice, Czech Republic, Czechia, 625 00
      • Novartis Investigative Site
    • Liberec, Czech Republic, Czechia, 46063
      • Novartis Investigative Site
• Denmark
  • Aalborg, Denmark, DK 9000
    • Novartis Investigative Site
  • Aarhus, Denmark, DK-8000
    • Novartis Investigative Site
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
  • Herlev, Denmark, 2730
    • Novartis Investigative Site
  • Odense C, Denmark, DK 5000
    • Novartis Investigative Site
  • Vejle, Denmark, 7100
    • Novartis Investigative Site
• France
  • Besancon Cedex, France, 25030
    • Novartis Investigative Site
  • Bordeaux, France, 33076
    • Novartis Investigative Site
  • Bordeaux Cedex, France, 33000
    • Novartis Investigative Site
  • Brest, France, 29200
    • Novartis Investigative Site
  • Creteil, France, 94000
    • Novartis Investigative Site
  • Le Mans Cedex, France, 72015
    • Novartis Investigative Site
  • Lille Cedex, France, 59020
    • Novartis Investigative Site
  • Limoges, France, 87000
    • Novartis Investigative Site
  • Paris 13, France, 75651
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
  • Toulon La Seyne Sur Mer, France, 83056
    • Novartis Investigative Site
  • Cedex
    • Strasbourg, Cedex, France, 67000
      • Novartis Investigative Site
  • Hauts De Seine
    • Saint-Cloud, Hauts De Seine, France, 92210
      • Novartis Investigative Site
  • Marne
    • Reims, Marne, France, 51056
      • Novartis Investigative Site
• Germany
  • Augsburg, Germany, 86150
    • Novartis Investigative Site
  • Berlin, Germany, 10117
    • Novartis Investigative Site
  • Berlin, Germany, 10967
    • Novartis Investigative Site
  • Bielefeld, Germany, 33604
    • Novartis Investigative Site
  • Bonn, Germany, 53111
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Fuerth, Germany, 90766
    • Novartis Investigative Site
  • Hamburg, Germany, 22081
    • Novartis Investigative Site
  • Hamburg, Germany, 22767
    • Novartis Investigative Site
  • Hannover, Germany, 30559
    • Novartis Investigative Site
  • Heidelberg, Germany, 69115
    • Novartis Investigative Site
  • Koeln, Germany, 50935
    • Novartis Investigative Site
  • Luebeck, Germany, 23538
    • Novartis Investigative Site
  • Muenchen, Germany, 80637
    • Novartis Investigative Site
  • Mühlhausen, Germany, 99974
    • Novartis Investigative Site
  • Oldenburg, Germany, 26121
    • Novartis Investigative Site
  • Ravensburg, Germany, 88214
    • Novartis Investigative Site
  • Saarbruecken, Germany, 66113
    • Novartis Investigative Site
  • Troisdorf, Germany, 53840
    • Novartis Investigative Site
  • Tuebingen, Germany, 72076
    • Novartis Investigative Site
  • Velbert, Germany, 42551
    • Novartis Investigative Site
  • Weiden, Germany, 92637
    • Novartis Investigative Site
  • Hessen
    • Langen, Hessen, Germany, 63225
      • Novartis Investigative Site
  • Lower Saxony
    • Georgsmarienhuette, Lower Saxony, Germany, 49124
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1122
    • Novartis Investigative Site
  • Budapest, Hungary, 1134
    • Novartis Investigative Site
  • Budapest, Hungary, H-1032
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Szolnok, Hungary, H-5000
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • AQ
    • L'Aquila, AQ, Italy, 67100
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • CT
    • Catania, CT, Italy, 95124
      • Novartis Investigative Site
  • LE
    • Lecce, LE, Italy, 73100
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • PI
    • Pontedera, PI, Italy, 56025
      • Novartis Investigative Site
• Jordan
  • Amman, Jordan, 11941
    • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Novartis Investigative Site
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
• Malaysia
  • Johor
    • Johor Bahru, Johor, Malaysia, 81100
      • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Novartis Investigative Site
• Mexico
  • Oaxaca, Mexico, 68000
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
  • Breda, Netherlands, 4819 EV
    • Novartis Investigative Site
  • Den Haag, Netherlands, 2545 CH
    • Novartis Investigative Site
  • Deventer, Netherlands, 7416 SE
    • Novartis Investigative Site
  • Enschede, Netherlands, 7513 ER
    • Novartis Investigative Site
  • Groningen, Netherlands, 9728 NZ
    • Novartis Investigative Site
  • Hoofddorp, Netherlands, 2134 TM
    • Novartis Investigative Site
  • Maastricht, Netherlands, 6229 HX
    • Novartis Investigative Site
  • Nieuwegein, Netherlands, 3435 CM
    • Novartis Investigative Site
  • Roermond, Netherlands, 6043 CV
    • Novartis Investigative Site
  • Sittard-Geleen, Netherlands, 6162 BG
    • Novartis Investigative Site
  • Tilburg, Netherlands, 5042 AD
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, NO 0424
    • Novartis Investigative Site
• Poland
  • Konin, Poland, 62 500
    • Novartis Investigative Site
  • Warszawa, Poland, 04-125
    • Novartis Investigative Site
• Portugal
  • Lisboa, Portugal, 1400-038
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Novartis Investigative Site
  • Tambov, Russian Federation, 392000
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Madrid, Spain, 28222
    • Novartis Investigative Site
  • Andalucia
    • Granada, Andalucia, Spain, 18014
      • Novartis Investigative Site
    • Madrid, Andalucia, Spain, 28046
      • Novartis Investigative Site
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41014
      • Novartis Investigative Site
  • Barcelona
    • Sant Joan Despi, Barcelona, Spain, 08970
      • Novartis Investigative Site
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
  • Galicia
    • A Coruna, Galicia, Spain, 15009
      • Novartis Investigative Site
  • Madrid
    • Alcorcon, Madrid, Spain, 28922
      • Novartis Investigative Site
    • San Sebastian de los Reyes, Madrid, Spain, 28702
      • Novartis Investigative Site
• Sweden
  • Eskilstuna, Sweden, SE-631 88
    • Novartis Investigative Site
  • Sundsvall, Sweden, 851 86
    • Novartis Investigative Site
  • Vaxjo, Sweden, SE-351 85
    • Novartis Investigative Site
• Switzerland
  • Aarau, Switzerland, 5000
    • Novartis Investigative Site
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8038
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
• Turkey
  • Istanbul, Turkey, 34303
    • Novartis Investigative Site
  • Istanbul, Turkey, 34662
    • Novartis Investigative Site
  • Istanbul, Turkey, 34381
    • Novartis Investigative Site
  • Izmir, Turkey, 35575
    • Novartis Investigative Site
• United Kingdom
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Novartis Investigative Site
  • Devon
    • Plymouth, Devon, United Kingdom, PL6 8DH
      • Novartis Investigative Site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Southern Cancer Center PC SC-2
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Ironwood Cancer and Research Centers SC-2
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group .
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center .
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation SC
    • Santa Rosa, California, United States, 94503
      • St Joseph Heritage Healthcare
  • Colorado
    • Fort Collins, Colorado, United States, 80528
      • Poudre Valley Hospital
  • Florida
    • Davie, Florida, United States, 33328
      • Florida Cancer Research Institute Dept of Oncology
    • Orlando, Florida, United States, 32806
      • UF Health Cancer Center at Orlando Health
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute SC
  • Georgia
    • Thomasville, Georgia, United States, 31792
      • John D Archbold Memorial Hospital Main
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Moanalua Medical Center. Attn: Oncology Dept SC
  • Illinois
    • Park Ridge, Illinois, United States, 60068-0736
      • Oncology Specialists, SC Advocate Medical Group-Niles
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Jackson Oncology Associates SC
  • New Jersey
    • Neptune, New Jersey, United States, 07753
      • Meridian Health Systems Regulatory
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Cancer Center SC
  • New York
    • Glens Falls, New York, United States, 12801
      • CR Wood Cancer Center SC
    • Lake Success, New York, United States, 11042
      • Clinical Research Alliance .
    • New York, New York, United States, 10016
      • NYU Langone Med Center CV Research NYU Langone Medical Center
  • Ohio
    • Zanesville, Ohio, United States, 43701
      • Genesis Cancer Services SC
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State University Milton S Hershey Medical Center SC
  • Texas
    • Houston, Texas, United States, 77090
      • Millennium Research Clin Develop SC
  • Utah
    • Ogden, Utah, United States, 84403-3105
      • Northern Utah Cancer Associates CFTY720DUS01
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Regional Cancer Partnership .
    • Lacey, Washington, United States, 98503
      • Providence Regional Cancer System SC
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center-Oncology SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ribociclib + fulvestrant; Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment.	Drug: Ribociclib; Ribociclib capsules were administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle.; Other Names: LEE011; Drug: 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 Comparator: Placebo + fulvestrant; Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment. Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant.	Drug: 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.; Drug: Placebo; Placebo capsules were administered orally for 21 consecutive days within a 28-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Burris HA, Chan A, Bardia A, Thaddeus Beck J, Sohn J, Neven P, Tripathy D, Im SA, Chia S, Esteva FJ, Hart L, Zarate JP, Ridolfi A, Lorenc KR, Yardley DA. Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer. Br J Cancer. 2021 Aug;125(5):679-686. doi: 10.1038/s41416-021-01415-9. Epub 2021 Jun 22.
• Yardley DA. MONALEESA clinical program: a review of ribociclib use in different clinical settings. Future Oncol. 2019 Aug;15(23):2673-2686. doi: 10.2217/fon-2019-0130. Epub 2019 Jul 15.
• Slamon DJ, Neven P, Chia S, Jerusalem G, De Laurentiis M, Im S, Petrakova K, Valeria Bianchi G, Martin M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Ji Y, Wang C, Deore U, Chakravartty A, Zarate JP, Taran T, Fasching PA. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021 Aug;32(8):1015-1024. doi: 10.1016/j.annonc.2021.05.353. Epub 2021 Jun 5. Erratum In: Ann Oncol. 2021 Oct;32(10):1307.
• Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Sondhi M, Wang Y, Chakravartty A, Rodriguez-Lorenc K, Taran T, Jerusalem G. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020 Feb 6;382(6):514-524. doi: 10.1056/NEJMoa1911149. Epub 2019 Dec 11.
• Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909. Epub 2018 Jun 3.
• Prat A, Chaudhury A, Solovieff N, Pare L, Martinez D, Chic N, Martinez-Saez O, Braso-Maristany F, Lteif A, Taran T, Babbar N, Su F. Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies. J Clin Oncol. 2021 May 1;39(13):1458-1467. doi: 10.1200/JCO.20.02977. Epub 2021 Mar 26. Erratum In: J Clin Oncol. 2021 Nov 1;39(31):3525. J Clin Oncol. 2023 Apr 20;41(12):2299-2301.

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2015
• Primary Completion (Actual): November 3, 2017
• Study Completion (Actual): January 11, 2023

Study Registration Dates

• First Submitted: April 1, 2015
• First Submitted That Met QC Criteria: April 16, 2015
• First Posted (Estimated): April 21, 2015

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Neoplasms; Phase III; LEE011; ribociclib; Antineoplastic Agents; Breast Neoplasms; Pharmacologic Actions; Men; Postmenopausal; Antineoplastic Agents, Hormonal; Neoplasms by Site; Breast Diseases; CDK4/6; HER2-negative; Advanced breast cancer; Molecular Mechanisms of Pharmacological Action; CDK4; CDK6; fulvestrant; CDK; ER-positive; PR-positive; Therapeutic Use; Estrogen Receptor Antagonists; Hormone Antagonists; CDK4/6 inhibitor; HR-positive; Hormones, Hormone Substitutes, and Hormone Antagonists; faslodex
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant
• Other Study ID Numbers: CLEE011F2301; 2015-000617-43 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No