Efficacy and Safety of Ribociclib in Pre- and Postmenopausal Chinese Women With HR Positive, HER2-negative, Advanced Breast Cancer.

Phase II Randomized, Double-blind, Placebo-controlled Study of LEE011(Ribociclib) or Placebo in Combination With Endocrine Therapy for the Treatment of Pre- and Postmenopausal Chinese Women With HR Positive, HER2-negative, Advanced Breast Cancer, Including a Subset With Pharmacokinetic Analysis.

This was a randomized, double-blind, placebo-controlled study conducted in Chinese women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer, plus an open-label, single-arm pharmacokinetic (PK) subset in postmenopausal Chinese women with HR+, HER2- advanced breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: NSAI: Letrozole or Anastrazole; Drug: Goserelin; Drug: Ribociclib; Drug: Ribociclib Placebo

Detailed Description

The study included three cohorts of subjects: a premenopausal cohort and a postmenopausal cohort, both randomized and double-blind, and an open-label, single-arm pharmacokinetic (PK) cohort of postmenopausal women.

The premenopausal cohort assessed the efficacy and safety of treatment with a non-steroidal aromatase inhibitor (NSAI; letrozole or anastrozole) combined with goserelin and ribociclib, compared with NSAI plus goserelin and placebo. The postmenopausal cohort assessed the efficacy and safety of ribociclib plus letrozole versus placebo plus letrozole.

The study consisted of three periods: screening, treatment, and follow-up.

1. Screening phase: The study began with a 28-day screening period during which potential participants were evaluated against inclusion and exclusion criteria before initiating treatment on Day 1.
2. Treatment phase: Eligible participants in the premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to one of two treatment arms, while participants in the PK cohort were not randomized. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Following a statistically significant progression-free survival (PFS) benefit observed at the primary analysis and implementation of Protocol Amendment 5 (dated 18-Oct-2022), participants and investigators were unblinded. Participants still receiving placebo were offered the option to cross over to ribociclib, at the investigator's discretion and with participant consent.

3. Follow-up phase:

   • Safety follow-up: All participants were followed for safety for up to 30 days after the last dose of study treatment, except in cases of death, loss to follow-up, or withdrawal of consent.
   • Efficacy follow-up: Tumor assessments were performed at baseline and every 8 weeks (±1 week) from randomization for the first 18 months, then every 12 weeks (±1 week) until 36 months, and thereafter as clinically indicated until progression. Participants who discontinued treatment for reasons other than disease progression continued tumor assessments according to the same schedule until progression, death, withdrawal of consent, or loss to follow-up.
   • Survival follow-up: Survival status was assessed every 12 weeks (±1 week) for all participants, regardless of treatment discontinuation reason, unless consent was withdrawn.

The end of the study was defined as the earliest occurrence of one of the following: all participants had discontinued or died; a new clinical study offering ribociclib became available and all ongoing participants were eligible for transfer; or participants still benefiting from treatment could continue receiving it through an alternative setting.

• Study Type: Interventional
• Enrollment (Actual): 327
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Fuzhou, China, 350001
    • Novartis Investigative Site
  • Qingdao, China, 266000
    • Novartis Investigative Site
  • Shanghai, China, 200032
    • Novartis Investigative Site
  • Shanghai, China, 200025
    • Novartis Investigative Site
  • Tianjin, China, 300480
    • Novartis Investigative Site
  • Anhui
    • Hefei, Anhui, China, 230001
      • Novartis Investigative Site
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100044
      • Novartis Investigative Site
  • Chongqing Municipality
    • Chongqing, Chongqing Municipality, China, 404100
      • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Novartis Investigative Site
  • Hebei
    • Shijiazhuang, Hebei, China, 050011
      • Novartis Investigative Site
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410013
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Novartis Investigative Site
    • Suzhou, Jiangsu, China, 215004
      • Novartis Investigative Site
  • Jiangxi
    • Nanchang, Jiangxi, China, 330009
      • Novartis Investigative Site
  • Jilin
    • Changchun, Jilin, China, 130021
      • Novartis Investigative Site
  • Liaoning
    • Shengyang, Liaoning, China, 110016
      • Novartis Investigative Site
    • Shengyang, Liaoning, China, 110042
      • Novartis Investigative Site
  • Shanxi
    • Xian, Shanxi, China, 710061
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Yunnan
    • Kunming, Yunnan, China, 650106
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310016
      • Novartis Investigative Site
    • Hangzhou, Zhejiang, China, 310006
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient has a histologically and/or cytologically confirmed diagnosis of estrogen receptor (ER) positive and/or progesterone receptor positive breast cancer by local laboratory (based on most recently analyzed biopsy).
• Patient has HER2-negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization test or an Immunohistochemistry (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.

• Patient must have either:

  • Measurable disease, i.e., at least 1 measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation). OR
  • If no measurable disease is present, then at least 1 predominantly lytic bone lesion must be present (patients with no measurable disease and only 1 predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).
• Patient has ECOG performance status 0 or 1.

For premenopausal cohort:

• Patient is an adult, female ≥ 18 years old and < 60 years old at the time of informed consent and has signed informed consent before any trial related activities are conducted and according to local guidelines.
• Confirmed negative serum pregnancy test before starting study treatment or patient has had a hysterectomy.
• Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer not amenable to curative therapy (e.g.

surgery and/or radiotherapy).

• Patients who received ≤ 14 days of a NSAI (letrozole or anastrozole) with or without goserelin or goserelin ≤ 28 days for advanced breast cancer prior to randomization are eligible. Patients must continue treatment with the same hormonal agent + goserelin during the study. No treatment interruption is required for these patients prior to randomization.
• Patients who have received up to 1 line of chemotherapy for advanced breast cancer and have been discontinued 28 days before randomization are eligible.

For postmenopausal cohort:

• Patient is an adult, female ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.
• Women with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.

Exclusion Criteria:

• Patient who has received a prior CDK4/6 inhibitor.
• Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment
• Patient with CNS metastases.
• Patient who has not had resolution of clinical and laboratory acute toxicities related to prior anti-cancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade ≤1.
• Patient has a known history of Human immunodeficiency Virus (HIV) infection (testing not mandatory).
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality
• Patient is currently receiving any of the substances as defined in the protocol that cannot be discontinued 7 days prior to the start of the treatment:

For premenopausal cohort:

• Pregnant or nursing (lactating) women.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment and for 21 days after stopping study medication.

Note: Use of oral (estrogen and progesterone), transdermal, injected or implanted hormonal methods of contraception as well as hormonal replacement therapy is not allowed in this study.

For postmenopausal cohort:

- Patient who received any prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy) for advanced breast cancer.

Note: Patients who received neo (adjuvant) therapy for breast cancer are eligible. If the prior neo (adjuvant) therapy included letrozole or anastrozole, the disease free interval must be greater than 12 months from the completion of treatment until randomization.

- Patients who received ≤ 14 days of letrozole or anastrozole for advanced disease prior to randomization are eligible.

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: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ribociclib; Patients in premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to either the experimental arm or the control arm. Premenopausal experimental arm: Non-steroidal aromatase inhibitor (NSAI) + Goserelin + Ribociclib. For premenopausal patients only, the patient was an adult female who was ≥ 18 years old and < 60 years old at the time of providing informed consent. The choice of non-steroidal aromatase inhibitor was based on the investigator's assessment of the patient's past medical history. Postmenopausal experimental arm: Letrozole + Ribociclib. Pharmacokinetic (PK) Cohort: Open-label treatment with Ribociclib + Letrozole combination. For postmenopausal patients only, the patient was an adult female who was ≥ 18 years old at the time of providing informed consent.	Drug: NSAI: Letrozole or Anastrazole; Letrozole: Tablets for oral use, 2.5mg daily (all days of every cycle without interruption). Anastrazole: Tablets for oral use, 1mg daily (all days of every cycle without interruption) For Premenopausal cohort, it is the investigators choice for NSAI based on patients past history. For postmenopausal and PK cohorts, all patients will be on Letrozole.; Drug: Goserelin; Subcutaneous implant, 3.6mg on Day 1 of each 28 day cycle; Drug: Ribociclib; Film-coated tablets for oral use (200 mg x 3) from days 1 to 21 of each 28 day cycle.; Other Names: LEE011
Placebo Comparator: Ribociclib Placebo; Patients in premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to either the experimental arm or the control arm. Premenopausal control arm: Non-steroidal aromatase inhibitor (NSAI) + Goserelin + Placebo. For premenopausal patients only, the patient was an adult female who was ≥ 18 years old and < 60 years old at the time of providing informed consent. The choice of non-steroidal aromatase inhibitor was based on the investigator's assessment of the patient's past medical history. Postmenopausal control arm: Letrozole + Placebo. For postmenopausal patients only, the patient was an adult female who was ≥ 18 years old at the time of providing informed consent.	Drug: NSAI: Letrozole or Anastrazole; Letrozole: Tablets for oral use, 2.5mg daily (all days of every cycle without interruption). Anastrazole: Tablets for oral use, 1mg daily (all days of every cycle without interruption) For Premenopausal cohort, it is the investigators choice for NSAI based on patients past history. For postmenopausal and PK cohorts, all patients will be on Letrozole.; Drug: Goserelin; Subcutaneous implant, 3.6mg on Day 1 of each 28 day cycle; Drug: Ribociclib Placebo; Film-coated tablets for oral use (200 mg x 3) from days 1 to 21 of each 28 day cycle.; Other Names: LEE011 Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pre and Postmenopausal Cohorts: Progressive Free Survival (PFS) Based on Local Assessment by RECIST 1.1 Guideline	Progression-free survival (PFS) was defined as the time from randomization to the first documented disease progression or death from any cause. PFS was assessed by local investigators based on tumor evaluations using RECIST version 1.1 criteria. Patients who had not experienced progression or death by the analysis cut-off date of 25 April 2022 were censored at the date of their last adequate tumor assessment prior to that cut-off.	After approximately 100 progression-free survival (PFS) events had been observed in each cohort, using data collected up to the analysis cut-off date of 25-Apr-2022, an average of 43 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK Cohort: Maximum Observed Plasma Concentration (Cmax) of Ribociclib and Its Metabolite LEQ803	Venous whole blood samples were collected for activity-based pharmacokinetic characterization. The maximum plasma concentration (Cmax) was listed and summarized using descriptive statistics. Actual sampling times were taken into consideration for the pharmacokinetic analysis.	Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
PK Cohort: Time to Maximum Observed Plasma Concentration (Tmax) of Ribociclib and Its Metabolite LEQ803	Venous whole blood samples were collected for activity-based pharmacokinetic characterization. The time to reach maximum plasma concentration (Tmax) was listed and summarized using descriptive statistics. Actual sampling times were taken into consideration for the pharmacokinetic analysis.	Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
PK Cohort: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24h) of Ribociclib and Its Metabolite LEQ803	Venous whole blood samples were collected for activity-based pharmacokinetic characterization. The area under the concentration-time curve from time zero to 24 hours post-dose (AUC₀-₂₄h) was listed and summarized using descriptive statistics. Actual sampling times were taken into consideration for the pharmacokinetic analysis.	Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
Pre and Postmenopausal Cohorts: Overall Survival (OS)	Overall Survival (OS) was defined as the time from date of first dose to date of death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date).	Up to approximately 80 months
Pre and Postmenopausal Cohorts: Overall Response Rate (ORR)	Overall Response Rate (ORR) was defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) by Investigator assessment as per RECIST 1.1 criteria: CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 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 80 months
Pre and Postmenopausal Cohorts: Clinical Benefit Rate (CBR)	Clinical Benefit Rate (CBR) was defined as the proportion of patients achieving a complete response (CR) or partial response (PR) per RECIST 1.1 criteria, or stable disease (SD) lasting at least 24 weeks, based on Investigator assessment using RECIST 1.1 criteria: CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 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 (PD).	Up to approximately 80 months
Pre and Postmenopausal Cohorts: Time To Response (TTR)	Time to Response (TTR) was defined as the duration from randomization to the first documented evidence of either a complete response (CR) (the disappearance of all target and non-target lesions) or a partial response (PR) (at least a 30% reduction in the sum of the longest diameters of target lesions from baseline) as assessed by the investigator.	Up to approximately 80 months
Pre and Postmenopausal Cohorts: Duration of Response (DoR)	Duration of Response (DoR) only applies to participants whose Best Overall Response (BOR) was complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date is 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 is defined as the date of the first documented progression or death due to any cause. Participants continuing without progression or death were censored at the date of their last adequate tumor assessment.	Up to approximately 80 months
Pre and Postmenopausal Cohorts: Time to Definitive Deterioration of ECOG Performance Status From Baseline	Time to definitive deterioration in ECOG performance status was defined as the time from the date of randomization to the date when ECOG performance status had definitively deteriorated by at least 1 category compared with baseline. Deterioration was considered definitive if there was no subsequent improvement in ECOG performance status back to the baseline category or above. The ECOG performance status scale assesses a patient's functional level, ranging from 0 (fully active) to 5 (dead). Patients were censored if no definitive deterioration in ECOG performance status was observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-neoplastic therapy was started. The censoring date was the date of the last performance status assessment prior to cut-off/start of new anti-neoplastic therapy. Time to definitive deterioration of ECOG performance status from baseline was estimated by using the Kaplan-Meier method.	Baseline up to approximately 43 months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2018
• Primary Completion (Actual): April 25, 2022
• Study Completion (Actual): May 9, 2025

Study Registration Dates

• First Submitted: September 12, 2018
• First Submitted That Met QC Criteria: September 12, 2018
• First Posted (Actual): September 14, 2018

Study Record Updates

• Last Update Posted (Actual): July 8, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: advanced breast cancer; pre- and postmenopausal Chinese women; Hormone receptor positive (HR+); Human epidermal growth factor receptor 2 negative (HER2-); ribociclib (LEE011); breast cancer (BC); endocrine therapy (ET)
• 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; Anastrozole; Goserelin; ribociclib
• Other Study ID Numbers: CLEE011A2206

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 review 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 availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

Drug and device information, study documents

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