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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01919229

Acronym

MONALEESA-1

Enrollment

Registered

2013-08-08

Start date

2013-10-31

Completion date

2014-09-30

Last updated

2016-01-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Early Breast Cancer

Keywords

HR-positive, HER2-negative, Breast cancer, LEE011, Letrozole, CDK, CDK4, CDK6, CDK4/6, Pharmacodynamics, Pre-surgical, Postmenopausal

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.

Interventions

DRUGLEE011 (ribociclib)

Ribociclib was supplied in 200 mg hard gelatin capsules for oral use.

DRUGletrozole

Letrozole was supplied in 2.5mg tablets for oral use.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

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/

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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	—
Safety and Tolerability of the Combination	Up to 30 days after the last dose	Occurrence, frequency and severity of adverse events (AEs), laboratory abnormalities
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	—
Change in ECG Morphology	Baseline, Day 14	—

Countries

Singapore, Spain, United States

Participant flow

Pre-assignment details

20 patients were screened, of those 14 patients completed the Screening phase and were randomized. 6 patients discontinued during the Screening phase; 3 patients were considered screen failure and 3 patients discontinued due to patient's decision.

Participants by arm

Arm	Count
Letrozole Letrozole 2.5 mg alone once daily	4
LEE011 400mg + Letrozole Letrozole 2.5 mg once daily and ribociclib 400 mg (2 capsules of 200 mg each) once daily.	6
LEE011 600mg + Letrozole Letrozole 2.5 mg once daily and ribociclib 600 mg (3 capsules of 200 mg each) once daily.	4
Total	14

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Subject/guardian decision	0	0	1

Baseline characteristics

Characteristic	Letrozole	LEE011 400mg + Letrozole	LEE011 600mg + Letrozole	Total
Age, Continuous	57.0 years STANDARD_DEVIATION 5.48	64.2 years STANDARD_DEVIATION 9.91	70.0 years STANDARD_DEVIATION 4.24	63.8 years STANDARD_DEVIATION 8.66
Age, Customized < 65 years	4 Participants	3 Participants	0 Participants	7 Participants
Age, Customized >=65 years	0 Participants	3 Participants	4 Participants	7 Participants
Sex: Female, Male Female	4 Participants	6 Participants	4 Participants	14 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	2 / 4	5 / 6	4 / 4
serious Total, serious adverse events	0 / 4	0 / 6	0 / 4

Outcome results

Primary

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.

Time frame: Day 1, Day15