E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HR+, HER2- early breast cancer |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To estimate the difference in anti-proliferative activity of LEE011 600 mg QD and LEE011 400 mg QD in combination with letrozole from baseline to time of surgery (day15) as determined by cell cycle response rate 2.5 mg QD vs single agent letrozole 2.5 mg QD as measured by changes in Ki-67 levels |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of the combination of LEE011 + letrozole as measured by frequency and severity of AEs, laboratory abnormalities.
2.To characterize the ECG effects of LEE011 at 400 mg and 600 mg QD in combination with letrozole
3. To assess pharmacodynamics markers related to the activity of LEE011 in breast cancer as measured by changes between baseline and posttreatment expression of markers such as- but not limited to- pRB and CDK1
4.To assess pharmacokinetics of LEE011 (and any relevant metabolites) and letrozole as measured by PK parameters, including but not limited to, Cmax, Tmax, AUClast for LEE011 (and any relevant metabolites) and letrozole. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 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.
2. 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 and
estradiol in the postmenopausal range.
3. Patient has a histologically (and/or cytologically) confirmed diagnosis
of estrogen-receptor positive and/or progesterone receptor positive
breast cancer by local laboratory.
4. Patient has a grade II or grade III invasive breast cancer
5. Patient has HER2 negative breast cancer defined as a negative in situ
hybridization test or an 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
6. Patient has at least one breast lesion with a diameter of ≥1.5 cm by
ultrasound.
7. Patient has an Eastern Cooperative Oncology Group (ECOG)
performance status 0 or 1 |
|
E.4 | Principal exclusion criteria |
1. Patient has received any prior therapy for breast cancer.
2. Patient has a concurrent malignancy or malignancy within 3 years of
randomization, with the exception of adequately treated, basal or
squamous cell carcinoma, non-melanomatous skin cancer or
curatively resected cervical cancer.
3. 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.
4. 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Cell cycle response rate 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 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Difference from baseline to time of surgery in levels of Ki-67 |
|
E.5.2 | Secondary end point(s) |
1. Frequency and severity of AEs, laboratoryabnormalities
2. Time matched, placebo corrected, change from baseline in QTc and other cardiac intervals, changes in ECG morphology, and correlation between the QTc interval change from baseline and plasma concentrations of LEE011 and/or any relevant metabolites
3. Changes between baseline and post-treatment expression of markers such as- but not limited to- pRB and CDK1
4. PK parameters, including but not limited to, Cmax, Tmax, AUClast for LEE011 (and any relevant metabolites) and letrozole. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Frequency of AEs
Day 0 - day 14 i.e Changes from baseline to day of surgery |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Italy |
Netherlands |
Spain |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study is defined as the time point when data collection will stop and the final analysis of the study will occur. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |