Clinical trial NCT01919229: A Pharmacodynamics Pre-surgical Study of LEE011 in Early Breast Cancer Patients (MONALEESA-1)
Official title: A Randomized Pre-surgical Pharmacodynamics Study to Assess the Biological Activity of LEE011 Plus Letrozole Versus Single Agent Letrozole in Primary Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Early Breast Cancer
Keywords: HR-positive
HER2-negative
Breast cancer
LEE011
Letrozole
CDK
CDK4
CDK6
CDK4/6
Pharmacodynamics
Pre-surgical
Postmenopausal
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-08-08
Enrollment: 14
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

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.

Eligibility criteria: 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

Primary outcomes:
measure: Cell Cycle Response Rate Per Cell Proliferation Marker Ki67
timeFrame: Day 1, Day15
Secondary outcomes:
measure: Safety and Tolerability of the Combination
timeFrame: Up to 30 days after the last dose
measure: Change From Baseline in Electrocardiogram (ECG) Parameters
timeFrame: Baseline, Day 14
measure: Change From Baseline in Expression of Retinoblastoma Protein (pRB)
timeFrame: Baseline, Day 15
measure: PK (Pharmacokinetics) Parameters, Including But Not Limited to, Cmax, Tmax, AUClast for LEE011 (and Any Relevant Metabolites) and Letrozole.
timeFrame: Days 1, 8, 14 and 15
measure: Change in ECG Morphology
timeFrame: Baseline, Day 14
measure: Correlation Between PK Concentrations and ECG Changes
timeFrame: Day 14
measure: Change From Baseline in Expression of Cyclin-Dependent Kinase 1 (CDK1)
timeFrame: Baseline, Day 15
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group SC
state: Arkansas
city: Los Angeles
country: United States
facility: University of California at Los Angeles UCLA SC
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital SC-9
state: Massachusetts
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Dept of MD Anderson (8)
state: Texas
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.