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

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

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

Study Overview

• Status: Terminated
• Conditions: Early Breast Cancer
• Intervention / Treatment: Drug: letrozole; Drug: LEE011 (ribociclib)

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08003
      • Novartis Investigative Site
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group SC
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles UCLA SC
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital SC-9
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Dept of MD Anderson (8)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Curigliano G, Gomez Pardo P, Meric-Bernstam F, Conte P, Lolkema MP, Beck JT, Bardia A, Martinez Garcia M, Penault-Llorca F, Dhuria S, Tang Z, Solovieff N, Miller M, Di Tomaso E, Hurvitz SA. Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study. Breast. 2016 Aug;28:191-8. doi: 10.1016/j.breast.2016.06.008. Epub 2016 Jun 20.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: August 2, 2013
• First Submitted That Met QC Criteria: August 6, 2013
• First Posted (Estimate): August 8, 2013

Study Record Updates

• Last Update Posted (Estimate): January 1, 2016
• Last Update Submitted That Met QC Criteria: November 30, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Breast cancer; LEE011; Pharmacodynamics; Postmenopausal; Letrozole; CDK4/6; HER2-negative; CDK4; CDK6; CDK; HR-positive; Pre-surgical
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: CLEE011A2201; 2013-002588-24 (EudraCT Number)