E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
postmenopausal women with HR+, HER2-negative advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
advanced metastatic breast cancer |
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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 | 18.0 |
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 determine whether treatment with ribociclib + fulvestrant prolongs progression free survival (PFS) compared to treatment with placebo + fulvestrant in postmenopausal women with HR+, HER2-negative breast cancer. |
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E.2.2 | Secondary objectives of the trial |
1. To determine whether treatment with ribociclib + fulvestrant prolongs overall survival (OS) compared to treatment with placebo + fulvestrant.
2. To evaluate the two treatment arms with respect to centrally assessed PFS
3. To evaluate the two treatment arms with respect to overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR) and duration of response (DOR).
4. To evaluate the two treatment arms with respect to time to deterioration of ECOG performance status.
5. To evaluate the safety and tolerability of ribociclib in combination with fulvestrant.
6. To evaluate patient reported outcomes for health-related quality of life in the two treatment arms.
7. To characterize the pharmacokinetics (PK) of ribociclib (and relevant metabolites) when given in combination with fulvestrant.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient is postmenopausal.
2. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory and has HER2-negative breast cancer.
3. Patient must have either measurable disease by RECIST 1.1 or at least one predominantly lytic bone lesion.
4. Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer.
Patients may be:
• newly diagnosed advanced breast cancer, treatment naïve
• relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease
• relapsed with documented evidence of progression on or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease
• relapsed with documented evidence of progression more than 12 months from completion of adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for metastatic disease
• newly diagnosed advanced breast cancer, then relapsed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor)
5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
6. Patient has adequate bone marrow and organ function |
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E.4 | Principal exclusion criteria |
1. Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator’s best judgment.
2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant or any CDK4/6 inhibitor.
3. Patient with inflammatory breast cancer at screening .
4. Patients with Child pugh scroe B or C
5. Patients has received prior neoadjuvant/adjuvant treatment with antracyclines at cumulative doses of 450mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin
6. Patient with CNS involvement unless they are at least 4 weeks from prior therapy completion to starting the study treatment and have stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases
7. Clinically significant, uncontrolled heart disease and/or recent cardiac events 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
• 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.
• Congenital long QT syndrome or family history of long QT syndrome
• Systolic Blood Pressure (SBP) >160 or <90 mmHg
• Bradycardia (heart rate < 50 at rest), by ECG or pulse.
• On screening, inability to determine the QTcF interval on the ECG (ie: unreadable or not interpretable) or QTcF >450 msec (using Fridericia’s correction). All as determined by screening ECG (mean of triplicate ECGs).
8. Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to star the treatment:
• Known strong inducers or inhibitors of CYP3A4/5,
• That have a known risk to prolong the QT interval or induce Torsades de Pointes.
• Those have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
• Herbal preparations/medications, dietary supplements |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is PFS, 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 according to RECIST 1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
final analysis around 26 months from the date of first patient randomized |
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E.5.2 | Secondary end point(s) |
1. Overall survival: Time from date of randomization to the date of death from any cause.
2. PFS per blinded independent review committee (BIRC) and RECIST 1.1 criteria
3. ORR: Proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1.
4. CBR: Percentage of patients with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1
5. TTR: Time from randomization to the first documented and confirmed response (complete response or partial response) as defined in RECIST 1.1
6. DOR: Time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1
7. ECOG: Time to definitive deterioration of ECOG performance status from baseline: Time to deterioration of ECOG performance Status.
8. 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
9. Time to 10% deterioration in the global health status/QOL scale score of the EORTC QLQ-C30: Patient reported outcomes for health related quality of life
10. A change from baseline in the global health status/QOL scale score of the EORTC QLQ-C30: Patient reported outcomes for health related quality of life
11. Summary statistics for PK parameters at steady state, including but not limited to Cmax, Tmax, Ctrough for ribociclib (and relevant metabolites) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 58 months from date of first patient randomized.
2. PFS per BIRC: up to approximately 26 months
3. ORR: up to approximately 26 months
4. CBR: up to approximately 26 months
5. TTR: up to approximately 26 months
6. DOR: up to approximately 26 months
7. ECOG performance status deterioration: up to approximately 26 months
8. safety and tolerability: up to approximately 26 months
9. 10% deterioration in QOL: up to approximately 26 months
10. change from baseline in QOL: up to approximately 26 months
11. summary statistics for PK parameters: up to approximately 26 month
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 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) | No |
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 | 19 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 146 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Colombia |
Czech Republic |
Denmark |
France |
Germany |
Hong Kong |
Hungary |
India |
Israel |
Italy |
Korea, Republic of |
Lebanon |
Malaysia |
Mexico |
Netherlands |
Norway |
Poland |
Portugal |
Russian Federation |
Saudi Arabia |
Singapore |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United Kingdom |
United States |
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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 for a given patient is defined as when the patient permanently
discontinues study treatment with ribociclib + fulvestrant or placebo + fulvestrant 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 | 4 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 20 |