E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HR+, HER2- advanced breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072737 |
E.1.2 | Term | Advanced breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 compare progression-free survival between LEE011 in combination with letrozole to placebo plus letrozole among postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease. |
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E.2.2 | Secondary objectives of the trial |
Key secondary:
- To compare the two treatment arms with respect to overall survival.
Other secondary:
• To evaluate the two treatment arms with respect to overall response rate and clinical benefit rate
• To evaluate the two treatment arms with respect to time to deterioration of ECOG performance status
• To evaluate the safety and tolerability of LEE011 in combination with letrozole
• To evaluate patient reported outcomes for health-related quality of life in the two treatment arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Women with advanced (recurrent or metastatic) breast cancer who received no prior therapy for advanced disease.
2. Patient is postmenopausal. Postmenopausal status is defined either by:
• Prior bilateral oophorectomy
• Age ≥60
• Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range
Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status (NCCN Guidelines Version 2.2014). Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa) (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression in this trial.
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 HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.
5. Patient must have either:
• Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria (tumor lesions previously irradiated or subjected to ther locoregional therapy will only be considered measurable if disease progression at the treated site after completion of therapy is clearly documented) or,
• If no measurable disease is present, then at least one predominantly lytic bone lesion must be present (patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation)
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Other inclusion criteria as defined by protocol may apply. |
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E.4 | Principal exclusion criteria |
1. Patient who received any CDK4/6 inhibitor.
2. Patient who received any prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy) for advanced breast cancer.
Note:
• Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior (neo) adjuvant therapy included letrozole or anastrozole the disease free interval must be greater than 12 months from the completion of treatment until randomization.
• Patients who received ≤ 14 daysof letrozole or anastrazole for advanced disease prior to randomization are eligible
• Any prior (neo) adjuvant anti-cancer therapy must be stopped at least 5 half lives or 7 days, whichever is longer, before randomization
3. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment:
• That are known strong inducers or inhibitors of CYP3A4/5.
• That have a known risk to prolong the QT interval or induce Torsades de Pointes.
• That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
• herbal preparations/medications
4. 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.
5. 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 any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
arrhythmias, or conduction abnormality in the previous 12 months.
• On screening, 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 or <90 mmHg
Other exclusion criteria as defined by protocol may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via local radiology assessment according to RECIST 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
up to approximately 25 months |
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E.5.2 | Secondary end point(s) |
Key secondary:
- overall survival, defined as time from randomization to the date of death from any cause
Other secondary:
• ORR, defined as proportion of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST
• Clinical benefit rate (CBR), defined as the proportion of patients with a best overall repsonse of complete response (CR) or partial response (PR) or stable disease (SD) lasting more than 24 weeks as defined in RECIST 1.1
• time to definitive deterioration of ECOG performance status in one category of the score, defined as the time from date of randomization to the date of event, which is defined as at least one score lower than the baseline
• safety and tolerability of LEE001, determined by type, frequency and severity of Adverse Events per CTCAE version 4.03 and type, frequency and severity of laboratory toxicities per CTCAE version 4.03
• Time to definitive 10% deterioration in the global health status/QOL scale score of the EORTC QLQ-C30, defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the corresponding scale score (without further improvement above the threshold) or death due to any cause
• QTc interval, defined as time between the start of the Q wave and the of the T wave corrected for heart rate |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS: up to approximately 98 months
ORR: up to approximately 25 months
CBR: up to approximately 25 months
ECOG performance status deterioration: up to approximately 25.5 months
safety and tolerability: up to approximately 26 months
10% deterioration in QOL: up to approximately 25 months
QTc interval: baseline, cycle 1 day 15, cycle 2 day 1 and cycle 3 day 1 |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
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 |
Australia |
Brazil |
Canada |
Israel |
Japan |
Korea, Republic of |
Lebanon |
Russian Federation |
Singapore |
South Africa |
Taiwan |
Thailand |
Turkey |
United States |
Austria |
Belgium |
Denmark |
Finland |
France |
Germany |
Hungary |
Ireland |
Italy |
Netherlands |
Norway |
Spain |
Sweden |
United Kingdom |
Czechia |
Argentina |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The end of the study is defined as when the patient permanently discontinues treatment with LEE011 + letrozole or placebo + letrozole and all the end of trial procedures are completed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |