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

Phase 2

Terminated

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

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

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
LEE011 400 mg + letrozole	LEE011 (ribociclib)	Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily.
LEE011 600mg + letrozole	LEE011 (ribociclib)	Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily.
Letrozole	letrozole	Letrozole 2.5 mg alone once daily
LEE011 400 mg + letrozole	letrozole	Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily.
LEE011 600mg + letrozole	letrozole	Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily.

Primary Outcome Measures

Name	Time	Method
Cell Cycle Response Rate Per Cell Proliferation Marker Ki67	Day 1, Day15	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.

Secondary Outcome Measures

Name	Time	Method
Safety and Tolerability of the Combination	Up to 30 days after the last dose	Occurrence, frequency and severity of adverse events (AEs), laboratory abnormalities
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	Day 14	Correlation between the QTc interval change from baseline and plasma concentrations of LEE011 and/or any relevant metabolites
Change From Baseline in Expression of Cyclin-Dependent Kinase 1 (CDK1)	Baseline, Day 15

Locations (5): University of California at Los Angeles UCLA SC
🇺🇸
Los Angeles, California, United States
Massachusetts General Hospital SC-9
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Boston, Massachusetts, United States
University of Texas/MD Anderson Cancer Center Dept of MD Anderson (8)
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Houston, Texas, United States
Novartis Investigative Site
🇪🇸
Barcelona, Catalunya, Spain
Highlands Oncology Group SC
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Fayetteville, Arkansas, United States