| 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 | 19.0 |
| 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 |
|
| 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 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 assess treatment impact on patient reported outcome (PRO) measured by variations of Functional Assessment of Cancer Therapy – Breast (FACT-B) questionnaire scores
|
|
| 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, 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
4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
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 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 serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with well-documented Gilbert’s Syndrome
8. Patient must have a 12-lead ECG with 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. Subjects must be able to communicate with the investigator and comply with the requirements of the study procedures
|
|
| E.4 | Principal exclusion criteria |
1. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole
2. Patient who received any CDK4/6 inhibitor
3.Patient who received any prior systemic hormonal therapy for advanced breast cancer; no more than one prior regimen of chemotherapy for the treatment of metastatic disease is permitted
Note:
● Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior neo (adjuvant) included letrozole or anastrozole the disease free interval must be greater than 12 months from the completion of treatment until study entry.
● Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial are eligible.
● Any prior (neo) adjuvant anti-cancer therapy or prior chemotherapy for metastatic disease must be stopped at least 5 half-lives or 7 days, whichever is longer, before study inclusion.
4. Patient is concurrently using other anti-cancer therapy.
5. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
6. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 4.03 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
7. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation 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) and/or from whom ≥ 25% (Ellis R E 1961) of the bone marrow was irradiated.
8. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
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., 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 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 starting study drug:
● Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
● That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
● Herbal preparations/medications, dietary supplements
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 a prior investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence of 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
|
|
| 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 | 3 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Costa Rica |
| Czech Republic |
| Denmark |
| Egypt |
| Finland |
| France |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Lebanon |
| Malaysia |
| Mexico |
| Netherlands |
| Norway |
| Oman |
| Panama |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Saudi Arabia |
| Singapore |
| Slovakia |
| Slovenia |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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