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Study to Assess the Safety and Efficacy of Ribociclib (LEE011) in Combination With Letrozole for the Treatment of Men and Pre/Postmenopausal Women With HR+ HER2- aBC (COMPLEEMENT-1)

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ClinicalTrials.gov Identifier: NCT02941926
Recruitment Status : Active, not recruiting
First Posted : October 21, 2016
Results First Posted : May 9, 2022
Last Update Posted : May 9, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Breast Cancer
Interventions Drug: Ribociclib
Drug: Letrozole
Drug: Goserelin
Drug: Leuprolide
Enrollment 3246
Recruitment Details The study was conducted across 514 centers in 38 countries. The results presented are based on primary analysis approximately up to approximately 33 months (end of core phase). Data collection is still on-going and results of the extension phase will be provided after study completion.
Pre-assignment Details A total of 3694 participants were screened in this study of which 3246 participants were enrolled in the study
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Period Title: Overall Study
Started 3246
Canadian Sub-study [1] 88
Completed [2] 1301
Not Completed 1945
Reason Not Completed
Progressive disease             1109
Adverse Event             504
Subject/guardian decision             127
Physician Decision             112
Death             46
Protocol deviation             34
Lost to Follow-up             8
Technical problems             5
[1]
Participants who participated in the Canadian sub-study
[2]
Participants who completed treatment at the end of the Core Phase
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Overall Number of Baseline Participants 3246
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3246 participants
58.1  (12.22)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3246 participants
Female
3207
  98.8%
Male
39
   1.2%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3246 participants
Caucasian
2553
  78.7%
Unknown
284
   8.7%
Asian
227
   7.0%
Other
134
   4.1%
Black
29
   0.9%
Native American
18
   0.6%
Pacific Islander
1
   0.0%
1.Primary Outcome
Title Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase
Hide Description

AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s).

SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. A SAE which caused death of the participant was considered as fatal SAE.

AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE.

A participant with multiple severity grades for an AE is only counted under the maximum grade.

Time Frame From start of treatment up to 30 days after last treatment (for participants who did not enter to the Extension Phase) or up to last treatment in the Core Phase (for participants who entered the Extension Phase), assessed up to approximately 33 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set in the core phase: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core Phase.
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description:
Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Overall Number of Participants Analyzed 3246
Measure Type: Count of Participants
Unit of Measure: Participants
AEs- All grades
3203
  98.7%
AEs- Grade ≥ 3
2461
  75.8%
Treatment-related AEs- All grades
3091
  95.2%
Treatment-related AEs- Grade ≥ 3
2192
  67.5%
SAEs- All grades
702
  21.6%
SAEs- Grade ≥ 3
590
  18.2%
Treatment-related SAEs- All grades
203
   6.3%
Treatment-related SAEs- Grade ≥ 3
178
   5.5%
Fatal SAEs- All grades
62
   1.9%
Treatment-related Fatal SAEs- All grades
14
   0.4%
AEs leading to discontinuation- All grades
528
  16.3%
AEs leading to discontinuation- Grade ≥ 3
310
   9.6%
Treatment-related AEs leading to discontinuation- All grades
418
  12.9%
Treatment-related AEs leading to discontinuation-Grade ≥ 3
237
   7.3%
AEs leading to dose adjustment/interruption- All grades
2434
  75.0%
AEs leading to dose adjustment/interruption- Grade ≥ 3
2095
  64.5%
Treatment-related AEs leading to dose adjustment/interruption- All grades
2235
  68.9%
Treatment-related AEs leading to dose adjustment/interruption- Grade ≥ 3
1964
  60.5%
AEs requiring additional therapy- All grades
2624
  80.8%
AEs requiring additional therapy- Grade ≥ 3
844
  26.0%
Treatment-related AEs requiring additional therapy- All grades
1613
  49.7%
Treatment-related AEs requiring additional therapy- Grade ≥ 3
392
  12.1%
2.Secondary Outcome
Title Time-to-Progression (TTP) Based on Investigator's Assessment (Core Phase)
Hide Description

Time to progression (TTP) is defined as time from date of start of treatment to the date of first documented progression or death due to underlying cancer. Participants with symptoms of rapidly progressing disease without radiologic evidence were classified as progression only when clear evidence of clinical deterioration was documented and/or patient discontinued due to 'Disease progression' or death due to study indication. When there was no documentation of radiologic evidence of progression, and the patient discontinued for 'Disease progression' due to documented clinical deterioration of disease, the date of discontinuation was used as date of progression.

TTP was estimated using the Kaplan-Meier method. 95% CI of median was calculated according to Brookmeyer and Crowley method.

Time Frame Up to approximately 33 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis set: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core Phase.
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description:
Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Overall Number of Participants Analyzed 3246
Median (95% Confidence Interval)
Unit of Measure: Months
27.1 [1] 
(25.7 to NA)
[1]
Upper limit was not reached (NA) due to insufficient follow up time
3.Secondary Outcome
Title Overall Response Rate (ORR) Based on Investigator's Assessment (Core Phase)
Hide Description

Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's assessment.

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.

95% CI was calculated using the exact binomial method.

Time Frame Up to approximately 33 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis set: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core Phase.
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description:
Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Overall Number of Participants Analyzed 3246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
29.3
(27.7 to 30.9)
4.Secondary Outcome
Title Clinical Benefit Rate (CBR) Based on Investigator's Assessment (Core Phase)
Hide Description

Clinical benefit rate (CBR) is defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1 based on investigator's assessment.

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.

95% CI was calculated using the exact binomial method.

Time Frame Up to approximately 33 months
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis set: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core Phase.
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description:
Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Overall Number of Participants Analyzed 3246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
70.7
(69.1 to 72.2)
5.Secondary Outcome
Title Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase)
Hide Description

Change from baseline in FACT-B scores was assessed. FACT-B is a self-report instrument that measures multidimensional quality of life (QOL) in patients with breast cancer. The FACT-B consists of 37 questions that address physical, social, emotional, and functional well-being, with specific questions relevant to women with breast cancer. Each item has a score range of 0 (Not at all) to 4 (Very much), with a total score ranging from 0-148. The higher the score, the better the QOL reported by the participant. A positive change from baseline indicates improvement in QoL.

Due to the nature of the questionnaire, only females were asked to complete this questionnaire.

Time Frame On Day 1 of Cycle 1, 2, 3, 4 ,5, 6, 8, 10, 12 and after that every 3 cycles, and End of treatment, assessed up to 33 months. Cycle=28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Female participants in the Full Analysis set population for whom baseline and at least one post baseline patient-reported outcome measurements are available. Number analyzed indicates number of participants with available data for this outcome measure at specified timepoints.
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description:
Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Overall Number of Participants Analyzed 1230
Mean (Standard Deviation)
Unit of Measure: Score on a scale
Cycle 2 Day 1 Number Analyzed 1100 participants
0.2  (13.29)
Cycle 3 Day 1 Number Analyzed 993 participants
0.1  (13.72)
Cycle 4 Day 1 Number Analyzed 884 participants
-0.3  (14.90)
Cycle 5 Day 1 Number Analyzed 852 participants
0.0  (15.02)
Cycle 6 Day 1 Number Analyzed 839 participants
-0.8  (14.91)
Cycle 8 Day 1 Number Analyzed 726 participants
-0.9  (16.32)
Cycle 10 Day 1 Number Analyzed 683 participants
-1.2  (15.83)
Cycle 12 Day 1 Number Analyzed 680 participants
-1.6  (16.13)
Cycle 15 Day 1 Number Analyzed 602 participants
-2.0  (16.58)
Cycle 18 Day 1 Number Analyzed 538 participants
-2.0  (16.09)
Cycle 21 Day 1 Number Analyzed 473 participants
-2.0  (17.82)
Cycle 24 Day 1 Number Analyzed 289 participants
-3.0  (17.89)
Cycle 27 Day 1 Number Analyzed 145 participants
-2.7  (13.84)
Cycle 30 Day 1 Number Analyzed 32 participants
-2.0  (14.14)
Cycle 33 Day 1 Number Analyzed 2 participants
12.1  (21.10)
End of Treatment Number Analyzed 861 participants
-4.1  (16.98)
6.Secondary Outcome
Title Number of Participants With AEs and SAEs in the Extension Phase
Hide Description

AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s).

SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization.

AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE.

A participant with multiple severity grades for an AE is only counted under the maximum grade.

Time Frame From end of core phase up to approximately 18 months
Outcome Measure Data Not Reported
7.Secondary Outcome
Title Percentage of Participants With Clinical Benefit (Extension Phase)
Hide Description Clinical benefit as assessed by the Investigator
Time Frame From end of core phase up to approximately 18 months
Outcome Measure Data Not Reported
8.Other Pre-specified Outcome
Title Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole
Hide Description Exploratory analysis performed in archival tumor samples collected during screening in the main study. Protein expression levels of the ribociclib plus letrozole cohort that did not achieve clinical benefit (progression within 3 months of treatment) and the cohort sensitive to ribociclib and letrozole (cohort with a time to progression of 22 months or more) were determined using using Single-Pot, Solid-Phase-enhanced, Sample Preparation-Clinical Tissue Proteomics (SP3-CTP). For normalization purposes a pooled internal standard sample, comprised of aliquots of every sample included in the study, was included in each experimental batch. Protein abundances were calculated as the log2 transformed abundances relative to the pooled internal standard. Positive values represent higher protein expression levels compared to the pooled internal standard. Expression levels of proteins that showed association to predicting response to study treatment are presented.
Time Frame Screening (up to 28 days before first dose of study treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants included in the sub-study (only available for Canadian participants) with evaluable tumor samples collected during screening in the main study and with time to progression within 3 months (cohort not achieving clinical benefit) or with time to progression of 22 months or more (cohort sensitive to treatment)
Arm/Group Title Primary Resistance Cohort Sensitive Cohort
Hide Arm/Group Description:
Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who did not achieve clinical benefit (tumor progressed within 3 months of treatment)
Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Overall Number of Participants Analyzed 8 19
Mean (Standard Deviation)
Unit of Measure: log2 transformed relative ratio
Isocitrate dehydrogenase [NADP] cytoplasmic (IDH1) 0.112  (0.500) -0.218  (0.352)
Retinal dehydrogenase 1 (ALDH1A1) 0.022  (0.446) -0.325  (0.147)
Coagulation factor XIII A chain (F13A1) -0.378  (0.263) -0.010  (0.198)
Argininosuccinate synthase (ASS1) 0.104  (0.612) -0.466  (0.129)
Heat shock protein beta-1 (HSPB1) -0.546  (0.113) -0.151  (0.270)
Aldehyde dehydrogenase, mitochondrial (ALDH2) 0.319  (0.571) -0.077  (0.374)
Decorin (DCN) -0.456  (0.266) -0.033  (0.568)
Cathepsin G (CTSG) -0.634  (0.191) -0.175  (0.274)
Pyruvate carboxylase, mitochondrial (PC) 0.413  (0.649) -0.004  (0.181)
C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1) 0.033  (0.254) -0.129  (0.087)
Collagen alpha-3(VI) chain (COL6A3) -0.186  (0.187) -0.015  (0.186)
Versican core protein (VCAN) -0.301  (0.242) 0.141  (0.581)
Fibulin-1 (FBLN1) -0.245  (0.313) 0.128  (0.435)
Acetyl-CoA acetyltransferase, mitochondrial (ACAT1) 0.135  (0.409) -0.074  (0.136)
Long-chain-fatty-acid--CoA ligase 1 (ACSL1) 0.296  (1.056) -0.144  (0.205)
Pigment epithelium-derived factor (SERPINF1) -0.378  (0.161) 0.169  (0.662)
3-ketoacyl-CoA thiolase, mitochondrial (ACAA2) 0.258  (0.501) -0.080  (0.166)
Fatty acid synthase (FASN) -0.198  (0.198) 0.038  (0.284)
Lumican (LUM) -0.355  (0.182) 0.010  (0.399)
Fibulin-2 (FBLN2) -0.208  (0.098) 0.075  (0.271)
Prolow-density lipoprotein receptor-related protein 1 (LRP1) -0.148  (0.118) 0.094  (0.194)
Galectin-3-binding protein (LGALS3BP) -0.491  (0.134) -0.126  (0.213)
Inactive tyrosine-protein kinase 7 (PTK7) -0.251  (0.071) 0.070  (0.237)
Ras GTPase-activating-like protein IQGAP2 (IQGAP2) 0.318  (0.538) -0.036  (0.221)
Spectrin alpha chain, non-erythrocytic 1 (SPTAN1) 0.085  (0.323) -0.082  (0.123)
Periostin (POSTN) -0.419  (0.165) 0.051  (0.393)
Procollagen C-endopeptidase enhancer 1 (PCOLCE) -0.217  (0.172) 0.184  (0.375)
CD109 antigen (CD109) -0.213  (0.141) 0.043  (0.145)
Palladin (PALLD) -0.207  (0.137) 0.050  (0.221)
Collagen triple helix repeat-containing protein 1 (CTHRC1) -0.514  (0.156) 0.176  (0.387)
Collagen alpha-1(XII) chain (COL12A1) -0.302  (0.183) 0.230  (1.041)
Matrix-remodeling-associated protein 5 (MXRA5) -0.221  (0.192) 0.205  (0.431)
C-type mannose receptor 2 (MRC2) -0.201  (0.124) 0.170  (0.274)
Time Frame From start of treatment up to 30 days after last treatment (for participants who did not enter to the Extension Phase) or up to last treatment in the Core Phase (for participants who entered the Extension Phase), assessed up to 33 months.
Adverse Event Reporting Description Any sign or symptom that occurs during the study treatment up to 30 days post treatment (for participants who did not enter to the Extension Phase) or up to last treatment in the Core Phase (for participants who entered the Extension Phase)
 
Arm/Group Title Ribociclib + Letrozole + Goserelin/Leuprolide
Hide Arm/Group Description Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
All-Cause Mortality
Ribociclib + Letrozole + Goserelin/Leuprolide
Affected / at Risk (%)
Total   74/3246 (2.28%) 
Hide Serious Adverse Events
Ribociclib + Letrozole + Goserelin/Leuprolide
Affected / at Risk (%)
Total   702/3246 (21.63%) 
Blood and lymphatic system disorders   
Anaemia  1  24/3246 (0.74%) 
Coagulopathy  1  1/3246 (0.03%) 
Febrile neutropenia  1  21/3246 (0.65%) 
Leukopenia  1  3/3246 (0.09%) 
Lymph node pain  1  1/3246 (0.03%) 
Lymphadenopathy  1  1/3246 (0.03%) 
Lymphopenia  1  2/3246 (0.06%) 
Neutropenia  1  9/3246 (0.28%) 
Pancytopenia  1  2/3246 (0.06%) 
Thrombocytopenia  1  8/3246 (0.25%) 
Cardiac disorders   
Acute coronary syndrome  1  3/3246 (0.09%) 
Acute myocardial infarction  1  3/3246 (0.09%) 
Angina pectoris  1  2/3246 (0.06%) 
Aortic valve incompetence  1  1/3246 (0.03%) 
Arrhythmia  1  1/3246 (0.03%) 
Atrial fibrillation  1  7/3246 (0.22%) 
Atrial flutter  1  1/3246 (0.03%) 
Atrioventricular block  1  1/3246 (0.03%) 
Atrioventricular block complete  1  1/3246 (0.03%) 
Bradycardia  1  1/3246 (0.03%) 
Cardiac arrest  1  3/3246 (0.09%) 
Cardiac disorder  1  1/3246 (0.03%) 
Cardiac failure  1  3/3246 (0.09%) 
Cardiac failure acute  1  1/3246 (0.03%) 
Cardiac failure congestive  1  3/3246 (0.09%) 
Cardiopulmonary failure  1  1/3246 (0.03%) 
Cor pulmonale  1  1/3246 (0.03%) 
Coronary artery stenosis  1  1/3246 (0.03%) 
Left ventricular dysfunction  1  1/3246 (0.03%) 
Myocardial infarction  1  5/3246 (0.15%) 
Myocardial ischaemia  1  1/3246 (0.03%) 
Palpitations  1  1/3246 (0.03%) 
Supraventricular tachycardia  1  1/3246 (0.03%) 
Ventricular dysfunction  1  1/3246 (0.03%) 
Ear and labyrinth disorders   
Vertigo  1  2/3246 (0.06%) 
Vertigo positional  1  1/3246 (0.03%) 
Eye disorders   
Amaurosis fugax  1  1/3246 (0.03%) 
Cataract  1  1/3246 (0.03%) 
Eyelid ptosis  1  1/3246 (0.03%) 
Keratitis  1  1/3246 (0.03%) 
Retinal detachment  1  1/3246 (0.03%) 
Ulcerative keratitis  1  1/3246 (0.03%) 
Gastrointestinal disorders   
Abdominal distension  1  1/3246 (0.03%) 
Abdominal pain  1  16/3246 (0.49%) 
Abdominal pain upper  1  3/3246 (0.09%) 
Ascites  1  4/3246 (0.12%) 
Autoimmune colitis  1  1/3246 (0.03%) 
Colitis  1  3/3246 (0.09%) 
Constipation  1  6/3246 (0.18%) 
Diarrhoea  1  14/3246 (0.43%) 
Duodenal obstruction  1  1/3246 (0.03%) 
Duodenal perforation  1  1/3246 (0.03%) 
Enterovesical fistula  1  1/3246 (0.03%) 
Gastric haemorrhage  1  2/3246 (0.06%) 
Gastric ulcer  1  1/3246 (0.03%) 
Gastritis  1  1/3246 (0.03%) 
Gastrointestinal disorder  1  1/3246 (0.03%) 
Gastrointestinal haemorrhage  1  2/3246 (0.06%) 
Hernial eventration  1  1/3246 (0.03%) 
Ileus  1  2/3246 (0.06%) 
Intestinal obstruction  1  6/3246 (0.18%) 
Large intestinal haemorrhage  1  1/3246 (0.03%) 
Large intestinal obstruction  1  1/3246 (0.03%) 
Nausea  1  12/3246 (0.37%) 
Obstruction gastric  1  1/3246 (0.03%) 
Oesophageal obstruction  1  1/3246 (0.03%) 
Pancreatitis  1  2/3246 (0.06%) 
Pancreatitis acute  1  2/3246 (0.06%) 
Rectal haemorrhage  1  1/3246 (0.03%) 
Rectal stenosis  1  1/3246 (0.03%) 
Salivary gland calculus  1  1/3246 (0.03%) 
Small intestinal obstruction  1  2/3246 (0.06%) 
Splenic artery aneurysm  1  1/3246 (0.03%) 
Stomatitis  1  2/3246 (0.06%) 
Upper gastrointestinal haemorrhage  1  1/3246 (0.03%) 
Vomiting  1  31/3246 (0.96%) 
General disorders   
Adverse drug reaction  1  1/3246 (0.03%) 
Asthenia  1  6/3246 (0.18%) 
Chest discomfort  1  1/3246 (0.03%) 
Chills  1  1/3246 (0.03%) 
Death  1  1/3246 (0.03%) 
Disease progression  1  1/3246 (0.03%) 
Fatigue  1  5/3246 (0.15%) 
Gait disturbance  1  2/3246 (0.06%) 
General physical health deterioration  1  13/3246 (0.40%) 
Influenza like illness  1  1/3246 (0.03%) 
Infusion site extravasation  1  1/3246 (0.03%) 
Localised oedema  1  1/3246 (0.03%) 
Malaise  1  3/3246 (0.09%) 
Multiple organ dysfunction syndrome  1  2/3246 (0.06%) 
Non-cardiac chest pain  1  9/3246 (0.28%) 
Oedema  1  1/3246 (0.03%) 
Oedema peripheral  1  2/3246 (0.06%) 
Organ failure  1  1/3246 (0.03%) 
Pain  1  3/3246 (0.09%) 
Pelvic mass  1  1/3246 (0.03%) 
Peripheral swelling  1  1/3246 (0.03%) 
Pre-existing condition improved  1  1/3246 (0.03%) 
Pyrexia  1  25/3246 (0.77%) 
Stenosis  1  1/3246 (0.03%) 
Strangulated hernia  1  1/3246 (0.03%) 
Sudden death  1  1/3246 (0.03%) 
Hepatobiliary disorders   
Autoimmune hepatitis  1  1/3246 (0.03%) 
Bile duct stenosis  1  1/3246 (0.03%) 
Bile duct stone  1  1/3246 (0.03%) 
Biliary colic  1  1/3246 (0.03%) 
Biliary dilatation  1  1/3246 (0.03%) 
Cholecystitis  1  3/3246 (0.09%) 
Cholecystitis acute  1  4/3246 (0.12%) 
Cholelithiasis  1  5/3246 (0.15%) 
Drug-induced liver injury  1  1/3246 (0.03%) 
Hepatic failure  1  4/3246 (0.12%) 
Hepatic function abnormal  1  5/3246 (0.15%) 
Hepatitis  1  2/3246 (0.06%) 
Hepatitis acute  1  2/3246 (0.06%) 
Hepatitis toxic  1  1/3246 (0.03%) 
Hepatobiliary disease  1  1/3246 (0.03%) 
Hepatocellular injury  1  1/3246 (0.03%) 
Hepatotoxicity  1  4/3246 (0.12%) 
Hyperbilirubinaemia  1  2/3246 (0.06%) 
Jaundice  1  2/3246 (0.06%) 
Liver disorder  1  1/3246 (0.03%) 
Portal hypertension  1  1/3246 (0.03%) 
Immune system disorders   
Hypersensitivity  1  1/3246 (0.03%) 
Infections and infestations   
Abscess intestinal  1  1/3246 (0.03%) 
Arthritis bacterial  1  1/3246 (0.03%) 
Atypical pneumonia  1  1/3246 (0.03%) 
Bacterial infection  1  1/3246 (0.03%) 
Bartholinitis  1  1/3246 (0.03%) 
Biliary sepsis  1  1/3246 (0.03%) 
Breast abscess  1  1/3246 (0.03%) 
Breast cellulitis  1  2/3246 (0.06%) 
Bronchitis  1  2/3246 (0.06%) 
Cellulitis  1  10/3246 (0.31%) 
Cervicitis  1  1/3246 (0.03%) 
Clostridium difficile colitis  1  2/3246 (0.06%) 
Colonic abscess  1  1/3246 (0.03%) 
Dengue fever  1  1/3246 (0.03%) 
Device related infection  1  2/3246 (0.06%) 
Ear infection  1  1/3246 (0.03%) 
Empyema  1  1/3246 (0.03%) 
Encephalitis  1  1/3246 (0.03%) 
Erysipelas  1  9/3246 (0.28%) 
Escherichia infection  1  1/3246 (0.03%) 
Fracture infection  1  1/3246 (0.03%) 
Gallbladder empyema  1  1/3246 (0.03%) 
Gastroenteritis  1  5/3246 (0.15%) 
Gastroenteritis viral  1  1/3246 (0.03%) 
Gastrointestinal fungal infection  1  1/3246 (0.03%) 
Hepatic infection  1  1/3246 (0.03%) 
Hepatitis C  1  1/3246 (0.03%) 
Infection  1  1/3246 (0.03%) 
Infectious pleural effusion  1  1/3246 (0.03%) 
Influenza  1  12/3246 (0.37%) 
Intervertebral discitis  1  1/3246 (0.03%) 
Kidney infection  1  2/3246 (0.06%) 
Liver abscess  1  1/3246 (0.03%) 
Lower respiratory tract infection  1  1/3246 (0.03%) 
Lower respiratory tract infection bacterial  1  1/3246 (0.03%) 
Lymphangitis  1  3/3246 (0.09%) 
Mastitis  1  2/3246 (0.06%) 
Metapneumovirus infection  1  1/3246 (0.03%) 
Neutropenic sepsis  1  2/3246 (0.06%) 
Otitis media  1  1/3246 (0.03%) 
Pneumonia  1  35/3246 (1.08%) 
Pneumonia bacterial  1  1/3246 (0.03%) 
Pneumonia influenzal  1  1/3246 (0.03%) 
Post procedural infection  1  2/3246 (0.06%) 
Postoperative wound infection  1  2/3246 (0.06%) 
Pulmonary sepsis  1  1/3246 (0.03%) 
Pyelonephritis  1  3/3246 (0.09%) 
Pyelonephritis acute  1  1/3246 (0.03%) 
Respiratory tract infection  1  1/3246 (0.03%) 
Respiratory tract infection viral  1  1/3246 (0.03%) 
Sepsis  1  12/3246 (0.37%) 
Septic shock  1  2/3246 (0.06%) 
Sinusitis  1  1/3246 (0.03%) 
Skin infection  1  1/3246 (0.03%) 
Soft tissue infection  1  1/3246 (0.03%) 
Spinal cord infection  1  2/3246 (0.06%) 
Staphylococcal infection  1  1/3246 (0.03%) 
Streptococcal sepsis  1  1/3246 (0.03%) 
Tooth abscess  1  1/3246 (0.03%) 
Tooth infection  1  1/3246 (0.03%) 
Tracheobronchitis  1  1/3246 (0.03%) 
Upper respiratory tract infection  1  5/3246 (0.15%) 
Urinary tract infection  1  17/3246 (0.52%) 
Urosepsis  1  5/3246 (0.15%) 
Vascular device infection  1  2/3246 (0.06%) 
Viral infection  1  2/3246 (0.06%) 
Viral upper respiratory tract infection  1  1/3246 (0.03%) 
Wound infection  1  1/3246 (0.03%) 
Injury, poisoning and procedural complications   
Acetabulum fracture  1  1/3246 (0.03%) 
Ankle fracture  1  3/3246 (0.09%) 
Facial bones fracture  1  1/3246 (0.03%) 
Fall  1  2/3246 (0.06%) 
Femoral neck fracture  1  2/3246 (0.06%) 
Femur fracture  1  8/3246 (0.25%) 
Fibula fracture  1  1/3246 (0.03%) 
Foot fracture  1  1/3246 (0.03%) 
Fracture  1  1/3246 (0.03%) 
Hand fracture  1  1/3246 (0.03%) 
Head injury  1  2/3246 (0.06%) 
Hip fracture  1  10/3246 (0.31%) 
Humerus fracture  1  2/3246 (0.06%) 
Inflammation of wound  1  1/3246 (0.03%) 
Lower limb fracture  1  1/3246 (0.03%) 
Overdose  1  1/3246 (0.03%) 
Pelvic fracture  1  1/3246 (0.03%) 
Procedural pain  1  1/3246 (0.03%) 
Radiation pneumonitis  1  1/3246 (0.03%) 
Radiation skin injury  1  1/3246 (0.03%) 
Road traffic accident  1  1/3246 (0.03%) 
Spinal compression fracture  1  1/3246 (0.03%) 
Spinal fracture  1  4/3246 (0.12%) 
Tendon rupture  1  1/3246 (0.03%) 
Tibia fracture  1  1/3246 (0.03%) 
Toxicity to various agents  1  3/3246 (0.09%) 
Ulna fracture  1  1/3246 (0.03%) 
Upper limb fracture  1  1/3246 (0.03%) 
Wound  1  1/3246 (0.03%) 
Wrist fracture  1  2/3246 (0.06%) 
Investigations   
Alanine aminotransferase increased  1  23/3246 (0.71%) 
Aspartate aminotransferase increased  1  15/3246 (0.46%) 
Blood bilirubin increased  1  10/3246 (0.31%) 
Blood creatinine increased  1  2/3246 (0.06%) 
Electrocardiogram QT prolonged  1  1/3246 (0.03%) 
Electrocardiogram abnormal  1  1/3246 (0.03%) 
Electrocardiogram change  1  1/3246 (0.03%) 
General physical condition abnormal  1  3/3246 (0.09%) 
Glomerular filtration rate decreased  1  1/3246 (0.03%) 
Hepatic enzyme increased  1  4/3246 (0.12%) 
Mycoplasma test positive  1  1/3246 (0.03%) 
Neutrophil count decreased  1  6/3246 (0.18%) 
Platelet count decreased  1  3/3246 (0.09%) 
Transaminases increased  1  6/3246 (0.18%) 
Waist circumference increased  1  1/3246 (0.03%) 
White blood cell count decreased  1  1/3246 (0.03%) 
Metabolism and nutrition disorders   
Decreased appetite  1  2/3246 (0.06%) 
Dehydration  1  5/3246 (0.15%) 
Food intolerance  1  2/3246 (0.06%) 
Hypercalcaemia  1  8/3246 (0.25%) 
Hyperglycaemia  1  1/3246 (0.03%) 
Hypermagnesaemia  1  1/3246 (0.03%) 
Hypocalcaemia  1  4/3246 (0.12%) 
Hypoglycaemia  1  1/3246 (0.03%) 
Hypokalaemia  1  4/3246 (0.12%) 
Hyponatraemia  1  9/3246 (0.28%) 
Hypophosphataemia  1  1/3246 (0.03%) 
Iron deficiency  1  1/3246 (0.03%) 
Mineral metabolism disorder  1  1/3246 (0.03%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  8/3246 (0.25%) 
Back pain  1  21/3246 (0.65%) 
Bone pain  1  7/3246 (0.22%) 
Bursitis  1  1/3246 (0.03%) 
Foot deformity  1  1/3246 (0.03%) 
Groin pain  1  1/3246 (0.03%) 
Intervertebral disc protrusion  1  1/3246 (0.03%) 
Joint range of motion decreased  1  1/3246 (0.03%) 
Muscle rigidity  1  1/3246 (0.03%) 
Muscular weakness  1  6/3246 (0.18%) 
Musculoskeletal chest pain  1  1/3246 (0.03%) 
Musculoskeletal pain  1  2/3246 (0.06%) 
Neck pain  1  3/3246 (0.09%) 
Osteoarthritis  1  1/3246 (0.03%) 
Osteonecrosis of jaw  1  1/3246 (0.03%) 
Osteoporotic fracture  1  1/3246 (0.03%) 
Pain in extremity  1  9/3246 (0.28%) 
Pathological fracture  1  2/3246 (0.06%) 
Rhabdomyolysis  1  1/3246 (0.03%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Adenocarcinoma of the cervix  1  1/3246 (0.03%) 
Bladder cancer  1  1/3246 (0.03%) 
Breast cancer  1  6/3246 (0.18%) 
Breast cancer metastatic  1  1/3246 (0.03%) 
Breast cancer recurrent  1  1/3246 (0.03%) 
Cancer pain  1  4/3246 (0.12%) 
Clear cell renal cell carcinoma  1  1/3246 (0.03%) 
Colon cancer  1  1/3246 (0.03%) 
Ependymoma  1  1/3246 (0.03%) 
Hepatic cancer  1  1/3246 (0.03%) 
Invasive ductal breast carcinoma  1  1/3246 (0.03%) 
Leiomyoma  1  1/3246 (0.03%) 
Lipoma  1  1/3246 (0.03%) 
Lung neoplasm malignant  1  2/3246 (0.06%) 
Malignant neoplasm of pleura  1  2/3246 (0.06%) 
Malignant neoplasm progression  1  3/3246 (0.09%) 
Malignant pleural effusion  1  1/3246 (0.03%) 
Metastases to bone  1  1/3246 (0.03%) 
Metastases to central nervous system  1  1/3246 (0.03%) 
Metastases to spine  1  1/3246 (0.03%) 
Pancreatic carcinoma  1  1/3246 (0.03%) 
Squamous cell carcinoma of lung  1  1/3246 (0.03%) 
Squamous cell carcinoma of the tongue  1  1/3246 (0.03%) 
Transitional cell carcinoma  1  1/3246 (0.03%) 
Tumour associated fever  1  2/3246 (0.06%) 
Vulval cancer  1  1/3246 (0.03%) 
Nervous system disorders   
Altered state of consciousness  1  1/3246 (0.03%) 
Ataxia  1  1/3246 (0.03%) 
Brain oedema  1  1/3246 (0.03%) 
Cerebral cyst  1  1/3246 (0.03%) 
Cerebral haemorrhage  1  1/3246 (0.03%) 
Cerebrovascular accident  1  9/3246 (0.28%) 
Coma  1  1/3246 (0.03%) 
Dizziness  1  4/3246 (0.12%) 
Dysarthria  1  1/3246 (0.03%) 
Dystonia  1  1/3246 (0.03%) 
Encephalopathy  1  1/3246 (0.03%) 
Epilepsy  1  1/3246 (0.03%) 
Facial paresis  1  1/3246 (0.03%) 
Haemorrhagic stroke  1  1/3246 (0.03%) 
Headache  1  7/3246 (0.22%) 
Hepatic encephalopathy  1  1/3246 (0.03%) 
Ischaemic stroke  1  2/3246 (0.06%) 
Loss of consciousness  1  1/3246 (0.03%) 
Migraine  1  1/3246 (0.03%) 
Neuralgia  1  1/3246 (0.03%) 
Paraesthesia  1  1/3246 (0.03%) 
Paralysis recurrent laryngeal nerve  1  1/3246 (0.03%) 
Petit mal epilepsy  1  1/3246 (0.03%) 
Sciatica  1  3/3246 (0.09%) 
Seizure  1  3/3246 (0.09%) 
Speech disorder  1  1/3246 (0.03%) 
Spinal cord compression  1  1/3246 (0.03%) 
Syncope  1  6/3246 (0.18%) 
Thalamic infarction  1  1/3246 (0.03%) 
Transient ischaemic attack  1  2/3246 (0.06%) 
Tremor  1  2/3246 (0.06%) 
Product Issues   
Device breakage  1  1/3246 (0.03%) 
Device dislocation  1  1/3246 (0.03%) 
Device extrusion  1  1/3246 (0.03%) 
Psychiatric disorders   
Anxiety  1  2/3246 (0.06%) 
Apathy  1  1/3246 (0.03%) 
Confusional state  1  4/3246 (0.12%) 
Delirium  1  3/3246 (0.09%) 
Depression  1  3/3246 (0.09%) 
Mental status changes  1  1/3246 (0.03%) 
Nervousness  1  1/3246 (0.03%) 
Suicide attempt  1  2/3246 (0.06%) 
Renal and urinary disorders   
Acute kidney injury  1  12/3246 (0.37%) 
Bladder necrosis  1  1/3246 (0.03%) 
Chronic kidney disease  1  1/3246 (0.03%) 
Haematuria  1  1/3246 (0.03%) 
Hydronephrosis  1  5/3246 (0.15%) 
Nephritis  1  1/3246 (0.03%) 
Nephrolithiasis  1  4/3246 (0.12%) 
Prerenal failure  1  1/3246 (0.03%) 
Renal colic  1  1/3246 (0.03%) 
Renal failure  1  2/3246 (0.06%) 
Renal impairment  1  1/3246 (0.03%) 
Renal injury  1  1/3246 (0.03%) 
Renal tubular disorder  1  1/3246 (0.03%) 
Urinary retention  1  1/3246 (0.03%) 
Urinary tract obstruction  1  2/3246 (0.06%) 
Reproductive system and breast disorders   
Breast mass  1  1/3246 (0.03%) 
Breast pain  1  1/3246 (0.03%) 
Colpocele  1  1/3246 (0.03%) 
Female genital tract fistula  1  2/3246 (0.06%) 
Pelvic pain  1  1/3246 (0.03%) 
Respiratory, thoracic and mediastinal disorders   
Acute respiratory failure  1  3/3246 (0.09%) 
Asthma  1  1/3246 (0.03%) 
Asthmatic crisis  1  1/3246 (0.03%) 
Atelectasis  1  1/3246 (0.03%) 
Chronic obstructive pulmonary disease  1  3/3246 (0.09%) 
Cough  1  2/3246 (0.06%) 
Dyspnoea  1  45/3246 (1.39%) 
Dyspnoea exertional  1  1/3246 (0.03%) 
Emphysema  1  1/3246 (0.03%) 
Hypoxia  1  3/3246 (0.09%) 
Interstitial lung disease  1  2/3246 (0.06%) 
Lung infiltration  1  1/3246 (0.03%) 
Oropharyngeal pain  1  1/3246 (0.03%) 
Pleural effusion  1  34/3246 (1.05%) 
Pneumomediastinum  1  1/3246 (0.03%) 
Pneumonitis  1  8/3246 (0.25%) 
Pneumothorax  1  4/3246 (0.12%) 
Pulmonary congestion  1  1/3246 (0.03%) 
Pulmonary embolism  1  19/3246 (0.59%) 
Pulmonary oedema  1  2/3246 (0.06%) 
Respiratory distress  1  2/3246 (0.06%) 
Respiratory failure  1  8/3246 (0.25%) 
Respiratory gas exchange disorder  1  1/3246 (0.03%) 
Skin and subcutaneous tissue disorders   
Dermatitis allergic  1  1/3246 (0.03%) 
Petechiae  1  1/3246 (0.03%) 
Urticaria  1  2/3246 (0.06%) 
Social circumstances   
Menopause  1  3/3246 (0.09%) 
Vascular disorders   
Accelerated hypertension  1  1/3246 (0.03%) 
Aortic stenosis  1  1/3246 (0.03%) 
Embolism  1  2/3246 (0.06%) 
Hypotension  1  1/3246 (0.03%) 
Jugular vein embolism  1  1/3246 (0.03%) 
Peripheral arterial occlusive disease  1  1/3246 (0.03%) 
Phlebitis  1  2/3246 (0.06%) 
Superior vena cava syndrome  1  1/3246 (0.03%) 
Thrombophlebitis  1  1/3246 (0.03%) 
1
Term from vocabulary, MedDRA (22.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Ribociclib + Letrozole + Goserelin/Leuprolide
Affected / at Risk (%)
Total   3150/3246 (97.04%) 
Blood and lymphatic system disorders   
Anaemia  1  597/3246 (18.39%) 
Leukopenia  1  596/3246 (18.36%) 
Lymphopenia  1  165/3246 (5.08%) 
Neutropenia  1  1981/3246 (61.03%) 
Thrombocytopenia  1  254/3246 (7.83%) 
Gastrointestinal disorders   
Abdominal pain  1  213/3246 (6.56%) 
Abdominal pain upper  1  216/3246 (6.65%) 
Constipation  1  553/3246 (17.04%) 
Diarrhoea  1  684/3246 (21.07%) 
Dyspepsia  1  237/3246 (7.30%) 
Nausea  1  1160/3246 (35.74%) 
Stomatitis  1  291/3246 (8.96%) 
Vomiting  1  633/3246 (19.50%) 
General disorders   
Asthenia  1  627/3246 (19.32%) 
Fatigue  1  756/3246 (23.29%) 
Oedema peripheral  1  279/3246 (8.60%) 
Pyrexia  1  393/3246 (12.11%) 
Infections and infestations   
Nasopharyngitis  1  194/3246 (5.98%) 
Upper respiratory tract infection  1  191/3246 (5.88%) 
Urinary tract infection  1  195/3246 (6.01%) 
Investigations   
Alanine aminotransferase increased  1  523/3246 (16.11%) 
Aspartate aminotransferase increased  1  456/3246 (14.05%) 
Blood creatinine increased  1  199/3246 (6.13%) 
Electrocardiogram QT prolonged  1  217/3246 (6.69%) 
Neutrophil count decreased  1  623/3246 (19.19%) 
White blood cell count decreased  1  336/3246 (10.35%) 
Metabolism and nutrition disorders   
Decreased appetite  1  401/3246 (12.35%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  674/3246 (20.76%) 
Back pain  1  426/3246 (13.12%) 
Bone pain  1  225/3246 (6.93%) 
Musculoskeletal pain  1  205/3246 (6.32%) 
Myalgia  1  192/3246 (5.91%) 
Pain in extremity  1  263/3246 (8.10%) 
Nervous system disorders   
Dizziness  1  235/3246 (7.24%) 
Headache  1  458/3246 (14.11%) 
Psychiatric disorders   
Insomnia  1  274/3246 (8.44%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  492/3246 (15.16%) 
Dyspnoea  1  275/3246 (8.47%) 
Skin and subcutaneous tissue disorders   
Alopecia  1  638/3246 (19.65%) 
Dry skin  1  228/3246 (7.02%) 
Pruritus  1  431/3246 (13.28%) 
Rash  1  374/3246 (11.52%) 
Vascular disorders   
Hot flush  1  490/3246 (15.10%) 
Hypertension  1  227/3246 (6.99%) 
1
Term from vocabulary, MedDRA (22.1)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study director
Organization: Novartis Pharmaceuticals
Phone: + 1 862 778 8300
EMail: Novartis.email@Novartis.com
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT02941926    
Obsolete Identifiers: NCT03613220
Other Study ID Numbers: CLEE011A2404
2016-003467-19 ( EudraCT Number )
First Submitted: October 20, 2016
First Posted: October 21, 2016
Results First Submitted: April 11, 2022
Results First Posted: May 9, 2022
Last Update Posted: May 9, 2022