E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HR-positive, HER2-negative 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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10070575 |
E.1.2 | Term | Estrogen receptor positive breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10073289 |
E.1.2 | Term | Premenopausal 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 |
The primary objective of this study is to determine whether the overall response rate (ORR) in the experimental arm (400 mg) is non-inferior to the control arm (600 mg) based on local tumor assessments (RECIST version1.1) for all patients that have been treated for at least 6 months or have discontinued the study treatment. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objective is to evaluate QTc (with Fridericia's correction) prolongation in the experimental arm.
Other secondary objectives include safety and tolerability, progression-free survival, clinical benefit rate, time to response, duration of response, pharmacokinetics of ribociclib when given in combination with NSAI.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable to curative therapy.
•Patient has a histologically and/or cytologically confirmed diagnosis of ER-positive and/or PgR-positive breast cancer based on the most recently analyzed tissue sample, and all tested by local laboratory.
•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 and based on the most recently analyzed tissue sample.
•Patient must have measurable disease, i.e., at least one measurable lesion according to RECIST
version 1.1. (a lesion in a previously irradiated site may only be counted as a target lesion if there is clear evidence of progression since the irradiation).
•Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
•Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory:
-QTcF interval at screening < 450 ms (QT interval using Fridericia's correction)
-Mean resting heart rate 50 to 90 bpm (determined from the ECG)
•Women of childbearing potential (CBP), defined as all women physiologically capable of becoming
pregnant, must have confirmed negative serum pregnancy test (for β-hCG) within 14 days prior to
randomization.
•Women of CBP must be willing to use highly effective methods of contraception.
Please refer to Section 5.1 of the protocol for full details on inclusion criteria. |
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E.4 | Principal exclusion criteria |
•Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible
for endocrine therapy per the investigator's judgment.
•Patient who received any prior systemic anti-cancer therapy (including endocrine therapy, chemotherapy, prior CDK4/6 inhibitors) for aBC. Patients who received neo-/adjuvant therapy for
breast cancer are eligible.
•Patient is concurrently using other anti-cancer therapy.
•Patient has had major surgery within 14 days prior to starting study drug or has not recovered
from major toxicities.
•Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2
weeks prior to randomization, and has not recovered to grade 1 or better from related side effects
of such therapy (with the exception of alopecia or other toxicities not considered a safety risk
for the patient at investigator's discretion).
•Patient has a concurrent malignancy or malignancy within 3 years of the randomization date, with
the exception of adequately treated basal or squamous cell skin carcinoma, or curatively resected
cervical carcinoma in situ.
•Patients with central nervous system (CNS) involvement unless they meet specific stability
criteria.
•Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality.
•Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to
starting study drug, and has not fully recovered from side effects of such treatment.
Please refer to Section 5.2 of the protocol for details on exclusion criteria.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR). ORR is based on local tumor assessments (RECIST version 1.1) for all patients that have been treated for at least 6 months or have discontinued the study treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After all patients have been treated for 6 months or have discontinued study treatment. |
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E.5.2 | Secondary end point(s) |
-Δ QTcF at Cycle 1 Day 15 (at 2h post-dose) (Key Secondary Endpoint)
-Progression-free survival (PFS)
-Clinical benefit rate (CBR)
-Time to response (TTR)
-Duration of response (DOR)
-Pharmacokinetics (PK) of ribociclib: Cmax
-Pharmacokinetics (PK) of ribociclib: Tmax
-Pharmacokinetics (PK) of ribociclib: AUC0 - 24h
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After all patients have been treated for 6 months or have discontinued study treatment. |
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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 | No |
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 | Yes |
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 | 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 | No |
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 | 49 |
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 |
Brazil |
Canada |
Colombia |
Costa Rica |
India |
Jordan |
Peru |
South Africa |
Thailand |
United States |
Austria |
Finland |
France |
Lithuania |
Sweden |
Bulgaria |
Czechia |
Germany |
Belgium |
Hungary |
Portugal |
Russian Federation |
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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
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End of study will be declared as the earliest occurrence of one of the following:
-All patients have died or discontinued from the study or have been followed up for
approximately 3 years from randomization.
-Patients who in the opinion of the investigator are still deriving clinical benefit in this
study can continue provision of study treatment through an alternative setting.
-Another clinical study becomes available that can continue to provide ribociclib in this
patient population |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 30 |