Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer (AMALEE)

A Phase II, Multicenter, Randomized, Open-label Study to Evaluate the Safety and Efficacy of 400 mg of Ribociclib in Combination With Non-steroidal Aromatase Inhibitors for the Treatment of Pre- and Postmenopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease

The purpose of the study was to evaluate the safety and efficacy of a reduced ribociclib starting dose of 400 mg in combination with a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) for the treatment of pre- and postmenopausal women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer (aBC) who have received no prior therapy for advanced disease. Premenopausal women were required to receive goserelin in both treatment arms.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Goserelin; Drug: Anastrozole; Drug: Letrozole; Drug: Ribociclib

Detailed Description

Patients were assigned at visit Cycle 1 Day 1 to one of the following two treatment arms in a ratio of 1:1:

• Experimental arm: Ribociclib 400 mg (2 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of:

  • For postmenopausal women:

  • Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously

    • For premenopausal women:

  • Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.

• Control arm: Ribociclib 600 mg (3 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of:

  • For postmenopausal women:

    ~ Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously.

  • For premenopausal women:

    • Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.

Participants received study treatment until disease progression (radiologically documented according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

For participants who discontinued treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor assessments continued to be performed until disease progression, death, lost to follow-up, or withdrawal of consent (post-treatment efficacy follow-up).

• Study Type: Interventional
• Enrollment (Actual): 376
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • San Juan, Argentina, J5402DIL
    • Novartis Investigative Site
• Austria
  • Linz, Austria, 4010
    • Novartis Investigative Site
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Vienna, Austria, 1090
    • Novartis Investigative Site
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Novartis Investigative Site
• Belgium
  • Edegem, Belgium, 2650
    • Novartis Investigative Site
  • Namur, Belgium, 5000
    • Novartis Investigative Site
• Brazil
  • Goiânia, Brazil, 74605-070
    • Novartis Investigative Site
  • São José do Rio Preto, Brazil, 15090 000
    • Novartis Investigative Site
  • Rio Grande do Norte
    • Natal, Rio Grande do Norte, Brazil, 59075 740
      • Novartis Investigative Site
  • Santa Catarina
    • Florianópolis, Santa Catarina, Brazil, 88034 000
      • Novartis Investigative Site
  • São Paulo
    • São Paulo, São Paulo, Brazil, 04014-002
      • Novartis Investigative Site
    • São Paulo, São Paulo, Brazil, 01317 000
      • Novartis Investigative Site
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1756
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1303
    • Novartis Investigative Site
• Canada
  • Ontario
    • Cambridge, Ontario, Canada, N1R 3G2
      • Novartis Investigative Site
• Colombia
  • Bogotá, Colombia, 110221
    • Novartis Investigative Site
  • Bogotá, Colombia, 110131
    • Novartis Investigative Site
  • Montería, Colombia, 230002
    • Novartis Investigative Site
  • Cesar Department
    • Valledupar, Cesar Department, Colombia, 5602310
      • Novartis Investigative Site
  • Tolima Department
    • Ibagué, Tolima Department, Colombia, 730006
      • Novartis Investigative Site
• Costa Rica
  • San José, Costa Rica, 95008
    • Novartis Investigative Site
• Czechia
  • Prague, Czechia, 150 06
    • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 53
      • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00029
    • Novartis Investigative Site
  • Tampere, Finland, FIN-33521
    • Novartis Investigative Site
• France
  • Besançon, France, 25030
    • Novartis Investigative Site
  • Caen, France, 14021
    • Novartis Investigative Site
  • Clermont-Ferrand, France, 63011
    • Novartis Investigative Site
  • Lyon 08, France, 69373
    • Novartis Investigative Site
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Montpellier, France, 34298
    • Novartis Investigative Site
  • Saint-Herblain, France, 44805
    • Novartis Investigative Site
  • Strasbourg, France, F 67085
    • Novartis Investigative Site
  • Valenciennes, France, 59300
    • Novartis Investigative Site
• Germany
  • Augsburg, Germany, 86150
    • Novartis Investigative Site
  • Berlin, Germany, 13581
    • Novartis Investigative Site
  • Bonn, Germany, 53111
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Dresden, Germany, 01127
    • Novartis Investigative Site
  • Essen, Germany, 45136
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site
  • Weiden, Germany, 92637
    • Novartis Investigative Site
  • Hesse
    • Langen, Hesse, Germany, 63225
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1122
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Szolnok, Hungary, H-5000
    • Novartis Investigative Site
• India
  • Delhii, India, 110 085
    • Novartis Investigative Site
  • Mumbai, India, 400 012
    • Novartis Investigative Site
  • Chhattisgarh
    • Raipur, Chhattisgarh, India, 492001
      • Novartis Investigative Site
  • Maharashtra
    • Nagpur, Maharashtra, India, 441108
      • Novartis Investigative Site
  • Odisha
    • Bhubaneshwar, Odisha, India, 751007
      • Novartis Investigative Site
• Jordan
  • Amman, Jordan, 11941
    • Novartis Investigative Site
• Lithuania
  • Vilnius, Lithuania, LT-08660
    • Novartis Investigative Site
  • LTU
    • Kaunas, LTU, Lithuania, LT 50161
      • Novartis Investigative Site
• Peru
  • La Libertad
    • Trujillo, La Libertad, Peru, 13011
      • Novartis Investigative Site
  • Lima region
    • San Borja, Lima region, Peru, 41
      • Novartis Investigative Site
    • San Isidro, Lima region, Peru, 27
      • Novartis Investigative Site
    • San Miguel, Lima region, Peru, 32
      • Novartis Investigative Site
• Portugal
  • Lisbon, Portugal, 1400-038
    • Novartis Investigative Site
  • Loures, Portugal, 2674514
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russia
  • Arkhangelsk, Russia, 163045
    • Novartis Investigative Site
  • Moscow, Russia, 115478
    • Novartis Investigative Site
  • Moscow, Russia, 111123
    • Novartis Investigative Site
  • Saint Petersburg, Russia, 197758
    • Novartis Investigative Site
• South Africa
  • Cape Town, South Africa, 7500
    • Novartis Investigative Site
  • Johannesburg, South Africa, 2196
    • Novartis Investigative Site
  • Parktown, South Africa, 2193
    • Novartis Investigative Site
• Sweden
  • Stockholm, Sweden, SE-118 83
    • Novartis Investigative Site
  • Stockholm, Sweden, 112 19
    • Novartis Investigative Site
  • Uppsala, Sweden, 751 85
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Novartis Investigative Site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Southern Cancer Center Pc
  • California
    • Greenbrae, California, United States, 94904
      • Marin Cancer Care
  • Colorado
    • Longmont, Colorado, United States, 80501
      • Rocky Mountain Cancer Centers
  • Florida
    • Orlando, Florida, United States, 32804
      • Florida Retina Institute
  • Maryland
    • Baltimore, Maryland, United States, 21237-3998
      • Weinberg Cancer Institute at FSH
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Nebraska Hematology Oncology P C
    • Omaha, Nebraska, United States, 68154
      • Nebraska Cancer Specialists
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Comprehensive Cancer Cntr Of Nevada
  • New York
    • Albany, New York, United States, 12208
      • New York Oncology Hematology
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • The Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • Texas
    • Houston, Texas, United States, 77090
      • Millennium Research Clin Develop
    • McAllen, Texas, United States, 78503
      • Texas Oncology
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties

Participation Criteria

Eligibility Criteria

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

Description

Key inclusion criteria:

• Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable to curative therapy.
• Patient has a histologically and/or cytologically confirmed diagnosis of ER-positive and/or PgR-positive breast cancer based on the most recently analyzed tissue sample, and all tested by local laboratory.
• Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample.
• Patient must have measurable disease, i.e., at least one measurable lesion according to RECIST version 1.1. (a lesion in a previously irradiated site may only be counted as a target lesion if there is clear evidence of progression since the irradiation).
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

• Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory:

  • QTcF interval at screening < 450 ms (QT interval using Fridericia's correction)
  • Mean resting heart rate 50 to 90 bpm (determined from the ECG)
• Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant, must have confirmed negative serum pregnancy test (for β-hCG) within 14 days prior to randomization.
• Women of CBP must be willing to use highly effective methods of contraception.

Key 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 who received any prior systemic anti-cancer therapy(including endocrine therapy, chemotherapy, prior CDK4/6 inhibitors) for aBC. Patients who received neo-/adjuvant therapy for breast cancer are eligible.
• Patient is concurrently using other anti-cancer therapy.
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major toxicities.
• Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to randomization, 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). Patients in whom ≥
• 25% of the bone marrow has been previously irradiated are also excluded.
• Patient has a concurrent malignancy or malignancy within 3 years of the randomization date, with the exception of adequately treated basal or squamous cell skin carcinoma, or curatively resected cervical carcinoma in situ.
• Patients with central nervous system (CNS) involvement unless they meet specific stability criteria.
• Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
• Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, and has not fully recovered from side effects of such treatment.

Other protocol-defined Inclusion/Exclusion may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ribociclib 400 mg; Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women)	Drug: Goserelin; Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only); Drug: Anastrozole; Anastrozole 1 mg tablets for oral use QD continuously; Drug: Letrozole; Letrozole 2.5 mg tablets for oral use QD continuously; Drug: Ribociclib; Ribociclib (at a dosage of 400 mg or 600 mg) QD orally taken on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (days 22 to 28). Ribociclib was supplied as 200 mg tablets as individual patient supply packaged bottles.; Other Names: LEE011
Active Comparator: Ribociclib 600 mg; Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women)	Drug: Goserelin; Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only); Drug: Anastrozole; Anastrozole 1 mg tablets for oral use QD continuously; Drug: Letrozole; Letrozole 2.5 mg tablets for oral use QD continuously; Drug: Ribociclib; Ribociclib (at a dosage of 400 mg or 600 mg) QD orally taken on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (days 22 to 28). Ribociclib was supplied as 200 mg tablets as individual patient supply packaged bottles.; Other Names: LEE011

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by local investigators according to RECIST 1.1. 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 23.8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose)	Electrocardiogram (ECG) data was collected via 12-lead digital ECG machines. Change from baseline in the QT interval (a segment of the ECG that reflects the time it takes for the heart to repolarize after each heartbeat) was corrected for heart rate using Fridericia's formula (ΔQTcF).	Baseline and Cycle 1 Day 15 at 2 hours post-dose. Cycle = 28 days
Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax)	PK parameters were calculated by non-compartmental analysis. Cmax is the maximum observed plasma drug concentration after single dose administration.	Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax)	PK parameters were calculated by non-compartmental analysis. Tmax is the time to reach maximum observed plasma concentration. Actual recorded sampling times were considered for the calculations.	Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24)	PK parameters were calculated by non-compartmental analysis. AUC0-24 is the area under the plasma concentration-time curve from 0 to 24 hours	Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
Progression-free Survival (PFS)	Progression free survival (PFS) was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. PFS was censored if no PFS event was observed. The censoring date was 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 a local radiology assessment as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1.	Up to approximately 60 months
Clinical Benefit Rate (CBR)	Clinical benefit rate (CBR) was defined as the proportion of patients with a best overall response of complete response (CR), or partial response (PR), or an overall response of stable disease (SD), lasting for at least 24 weeks. CR, PR, and SD were defined as per local review as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1. A patient was considered to have SD for 24 weeks or longer if a SD response was recorded at 24-1=23 weeks or later from randomization, allowing for the ±1 week visit window for tumor assessments. 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 60 months
Time to Response (TTR)	Time to response (TTR) was defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which had to be subsequently confirmed (although the date of initial response was used, not the date of confirmation). CR and PR were based on tumor response data as per local review and according to RECIST 1.1. 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 60 months
Duration of Response (DOR)	Duration of response (DOR) only applied to patients whose best overall response was complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date was the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date was defined as the date of the first documented progression or death due to underlying cancer. Patients continuing without progression or death due to underlying cancer were censored at the date of their 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.	Up to approximately 60 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Cardoso F, Jacot W, Kuemmel S, Gupta S, Cruz F, Balaraman R, Ferreira A, Ahola T, Chapko Y, Zhukova L, Chiang W, Li Z, Ji Y, Kaakiou N, Bolotova N, Sparano JA. 600- vs 400-mg First-Line Ribociclib in Hormone Receptor-Positive/ERBB2-Negative Advanced Breast Cancer: The AMALEE Randomized Clinical Trial. JAMA Oncol. 2025 Sep 25. doi: 10.1001/jamaoncol.2025.3687. Online ahead of print.

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2019
• Primary Completion (Actual): June 11, 2021
• Study Completion (Actual): August 30, 2024

Study Registration Dates

• First Submitted: January 28, 2019
• First Submitted That Met QC Criteria: January 28, 2019
• First Posted (Actual): January 30, 2019

Study Record Updates

• Last Update Posted (Estimated): October 16, 2025
• Last Update Submitted That Met QC Criteria: October 8, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: postmenopausal; premenopausal; HER2-negative; ER-positive; HR-positive; Breast Cancer (BC); human epidermal growth factor receptor 2 (HER2); hormone receptor (HR); advanced breast cancer (aBC); ribociclib (LEE011)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Nitriles; Triazoles; Gonadotropin-Releasing Hormone; Letrozole; Anastrozole; Goserelin; ribociclib
• Other Study ID Numbers: CLEE011A2207; 2018-004234-15 (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