| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hormone positive HER2 negative advanced Breast Cancer |
|
| 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 |
|
| 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 evaluate the safety and tolerability of ribociclib with letrozole in men and pre/postmenopausal women with HR+, HER2- aBC who received no prior hormonal therapy for advanced disease |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the clinical efficacy of ribociclib + letrozole measured by Time-to-Progression (TTP) and tumor response by overall response rate (ORR) and clinical benefit rate (CBR).
• To evaluate long-term safety of ribociclib + letrozole during Extension Phase
• To evaluate clinical benefit of ribociclib + letrozole as assessed by investigator during Extension Phase
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is an adult, male or female ≥ 18 years old at the time of informed consent
NOTE: Sexually active males should use a condom during intercourse while taking drug and for 21 days after stopping medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
2. Male or female with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
3. In the case of women, both pre/perimenopausal and postmenopausal patients are allowed to be included in this study; menopausal status is relevant for the requirement of goserelin or leuprolid to be used concomitantly with ribociclib and letrozole..
a) Postmenopausal status is defined either by:
● Prior bilateral oophorectomy OR
● Age ≥ 60 OR
● 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. If patient is taking tamoxifen or toremifene and age < 60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range.
b) Premenopausal status is defined as either:
i) Patient had last menstrual period within the last 12 months, OR
ii) If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, OR
iii) In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.
c) Perimenopausal status is defined as neither premenopausal nor postmenopausal
4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory. A confirmatory biopsy is not required.
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 is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
7. Patient has adequate bone marrow and organ function as defined by ALL of the following laboratory values (as assessed by local laboratory):
● Absolute neutrophil count ≥ 1.5 × 109/L
● Platelets ≥ 100 × 109/L
● Hemoglobin ≥ 9.0 g/dL
● Potassium, sodium, calcium corrected for serum albumin and magnesium within normal limits or corrected to within normal limits with supplements before first dose of the study medication
● INR ≤ 1.5
● Serum creatinine < 1.5 mg/dl or creatinine clearance ≥ 50 mL/min
● In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 × ULN. If the patient has liver metastases, ALT and AST should be < 5 × ULN.
● Total bilirubin < ULN except for patients with Gilbert's Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN
8. Patient must have a 12-lead ECG with ALL of the following parameters at screening:
● QTcF interval at screening < 450 msec (using Fridericia’s correction)
● Resting heart rate ≥ 50 bpm
9. Patient must be able to swallow ribociclib and letrozole tablets
10. Patient has signed informed consent obtained before any trial-related activities and according to local guidelines
11. Patients must be able to communicate with the investigator and comply with the requirements of the study procedures
|
|
| E.4 | Principal exclusion criteria |
7. Patient who has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy for palliation ≤ 2 weeks prior to start of treatment, and who 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 the investigator's discretion). Patients from whom ≥ 25% (Ellis R E 1961) of the bone
marrow has been previously irradiated are also excluded (see Appendix 14.4).
9. Patient with central nervous system (CNS) metastases unless they meet ALL of the following criteria:
● At least 4 weeks from prior therapy for CNS disease completion (including radiation and/or surgery) to starting the study treatment.
● Clinically stable CNS lesions at the time of study treatment initiation and not receiving steroids and/or enzyme-inducing anti-epileptic medications for the management of brain metastases for at least 2 weeks.
10. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
11. Patient has a known history of HIV infection (testing not mandatory)
12. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol: (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal,bacterial or viral infections, etc.)
13. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including but not limited to any of the following:
● History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty,or stenting) or symptomatic pericarditis within 6 months prior to screening
● History of documented congestive heart failure (New York Heart Association functional classification III-IV)
● Documented cardiomyopathy
● Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
● Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome,
● Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening
14. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to Cycle 1 Day1:
● comcomitant medications, herbal supplements, and/or fruits (e.g.grapefruit, pummeloes, star fruit, Seville oranges) and their juices known as strong inducers or inhibitors of CYP3A4/5
● medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
15. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
16. Participation in prior investigational study within 30 d prior to enrollment or within 5-half-lives of the investigational product,whichever is longer
17. Pregnant or nursing (lactating) women
Note: Women of child-bearing potential is defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 21 days after
stopping your study medication.
Highly effective contraception methods include:
● Total abstinence, when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods), and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy (surgical removal of the uterus and cervix) or tubal ligation (getting the "tubes tied") at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
● Male partner sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient
Placement of an intrauterine device (IUD) or intrauterine system (IUS)
Note: Use of oral (estrogen and progesterone), transdermal, injected, or implanted hormone containing intrauterine (IUS) or any other hormonal methods of contraception is not allowed in this study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| AEs, Grade 3/4 AEs & SAEs during treatment with ribociclib + letrozole |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| refer to section 10.4. of the protocol |
|
| E.5.2 | Secondary end point(s) |
• Time-to-Progression (TTP) (RECIST 1.1), based on investigators’ assessment
• Overall response rate (ORR) as defined by RECIST 1.1 for patients with measurable disease
• Clinical Benefit Rate (CBR) as defined by RECIST 1.1 (including patients with CR, PR, SD, NCRNPD >24 weeks)
• Patient Reported Outcome (PRO) using FACT-B questionnaire
• Frequency and severity of AEs & SAEs during Extension Phase
• Proportion of patients with clinical benefit as assessed by investigator during Extension Phase |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| refer to section 10.5.1 of the protocol |
|
| 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 | No |
| 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 |
| Patient Reported Outcome (PRO) |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 300 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| Egypt |
| Finland |
| France |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Lebanon |
| Luxembourg |
| Malaysia |
| Mexico |
| Netherlands |
| Norway |
| Oman |
| Panama |
| Philippines |
| Poland |
| Portugal |
| Russian Federation |
| Saudi Arabia |
| Singapore |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| United Arab Emirates |
| United Kingdom |
| United States |
| Jordan |
|
| 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
|
| Planned overall study duration of the Core Phase will be from FPFV to 18 months after LPFV. At the time of Core Phase end, if patients are still deriving benefit and ribociclib is not approved or available and reimbursed, patients may be transitioned to the extension trial period. The duration of the extension phase will be addressed in a future amendment. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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