A Pharmacodynamics Pre-surgical Study of LEE011 in Early Breast Cancer Patients (MONALEESA-1)

Study Overview
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Brief Summary
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This is a multi-center, open-label Phase II randomized pre-surgical pharmacodynamics study.

Detailed Description
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This randomized pre-surgical pharmacodynamics study will assess the biological activity of LEE011 plus letrozole versus single agent letrozole in primary breast cancer.

Official Title
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A Randomized Pre-surgical Pharmacodynamics Study to Assess the Biological Activity of LEE011 Plus Letrozole Versus Single Agent Letrozole in Primary Breast Cancer

Conditions
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Early Breast Cancer

Intervention / Treatment
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* Drug: LEE011 (ribociclib)
* Drug: letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patient is ≥ 18 years old at the time of informed consent, with newly diagnosed resectable breast cancer, who received no prior therapy for breast cancer Patient is postmenopausal. Postmenopausal status is defined either by: Prior bilateral oophorectomy Age ≥60 Age <60 and amenorrhea for 12 or more months and FSH (Follicle Stimulating Hormone) and estradiol in the postmenopausal range. Patient has a histologically (and/or cytologically) confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory. Patient has a grade II or grade III invasive breast cancer Patient has Human Epidermal Growth Factor Receptor 2 (HER2) negative breast cancer defined as a negative in situ hybridization test or an Immunohistochemistry (IHC) status of 0, 1+ or 2+ (if IHC 2+, a negative in situ hybridization (respectively FISH/CISH/SISH) test is required) by local laboratory testing Patient has at least one breast lesion with a diameter of ≥1.0 cm by the most accurate imaging modality used. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Exclusion Criteria: Patient has received any prior therapy for breast cancer. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal cell skin cancer or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. Patient has active cardiac disease or a history of cardiac dysfunction including any of the following: History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry History of documented congestive heart failure (New York Heart Association functional classification III-IV) Documented cardiomyopathy Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) History of ventricular, supraventricular, nodal arrhythmias, or any other cardiac arrhythmias, Long QT Syndrome or conduction abnormality in the previous 12 months. Family history of QTc prolongation or of unexplainable sudden death at <50 years of age. On screening 12 lead ECG, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec. Systolic blood pressure >160 mmHg or <90 mmHg. Patient is currently receiving any of the following medications (see Appendix 1 for details): That are known strong inducers or inhibitors of CYP3A4. That have a narrow therapeutic window and are predominantly metabolized through CYP3A4. That have a known risk to prolong the QT interval or induce Torsades de Pointes. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Letrozole<br>Letrozole 2.5 mg alone once daily | Drug: letrozole<br>* Letrozole was supplied in 2.5mg tablets for oral use.<br>|
| Experimental: LEE011 400 mg + letrozole<br>Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily. | Drug: LEE011 (ribociclib)<br>* Ribociclib was supplied in 200 mg hard gelatin capsules for oral use.<br>* Other names: ribociclib;Drug: letrozole<br>* Letrozole was supplied in 2.5mg tablets for oral use.<br>|
| Experimental: LEE011 600mg + letrozole<br>Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily. | Drug: LEE011 (ribociclib)<br>* Ribociclib was supplied in 200 mg hard gelatin capsules for oral use.<br>* Other names: ribociclib;Drug: letrozole<br>* Letrozole was supplied in 2.5mg tablets for oral use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cell Cycle Response Rate Per Cell Proliferation Marker Ki67 | Cell cycle response rate is defined by proportion of patients with natural logarithm of Ki-67 levels (expressed as percentage of baseline values) of less than 1 at the time of surgery. Since the trial was prematurely terminated, no statistical analysis was done. | Day 1, Day15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of the Combination | Occurrence, frequency and severity of adverse events (AEs), laboratory abnormalities | Up to 30 days after the last dose | 
| Change From Baseline in Electrocardiogram (ECG) Parameters |  | Baseline, Day 14 | 
| Change From Baseline in Expression of Retinoblastoma Protein (pRB) |  | Baseline, Day 15 | 
| PK (Pharmacokinetics) Parameters, Including But Not Limited to, Cmax, Tmax, AUClast for LEE011 (and Any Relevant Metabolites) and Letrozole. |  | Days 1, 8, 14 and 15 | 
| Change in ECG Morphology |  | Baseline, Day 14 | 
| Correlation Between PK Concentrations and ECG Changes | Correlation between the QTc interval change from baseline and plasma concentrations of LEE011 and/or any relevant metabolites | Day 14 | 
| Change From Baseline in Expression of Cyclin-Dependent Kinase 1 (CDK1) |  | Baseline, Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HR-positive, HER2-negative, Breast cancer, LEE011, Letrozole, CDK, CDK4, CDK6, CDK4/6, Pharmacodynamics, Pre-surgical, Postmenopausal