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    EudraCT Number:2016-003467-19
    Sponsor's Protocol Code Number:CLEE011A2404
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-01-12
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2016-003467-19
    A.3Full title of the trial
    COMPLEEMENT-1: An open-label, multicenter, Phase IIIb study to assess the safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with hormone receptorpositive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    COMPLEEMENT-1: Otvorené, multicentrické klinické skúšanie fázy IIIb na zhodnotenie bezpečnosti a účinnosti ribociclibu (LEE011) v kombinácii s letrozolom v liečbe mužov a pre/postmenopauzálnych žien s HER2-negatívnym (HER2-) pokročilým karcinómom prsníka s pozitívnymi hormonálnymi receptormi (HR+) bez predchádzajúcej hormonálnej terapie pre pokročilé ochorenie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and postmenopausal women with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberCLEE011A2404
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Slovakia s.r.o.
    B.5.2Functional name of contact pointDRA information desk
    B.5.3 Address:
    B.5.3.1Street AddressŽižkova 22B
    B.5.3.2Town/ cityBratislava
    B.5.3.3Post code811 02
    B.5.4Telephone number +421 2 50706116
    B.5.5Fax number +421 2 50706100
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Kisqali
    D. of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameribociclib
    D.3.2Product code LEE011
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRIBOCICLIB
    D.3.9.1CAS number 1374639-75-4
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB180246
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    E.1.1.1Medical condition in easily understood language
    Hormone positive HER2 negative advanced Breast Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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 bilrubin 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 trialrelated 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.4Principal exclusion criteria
    1. 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).
    2. 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.
    3. 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)
    4. Patient has a known history of HIV infection (testing not mandatory)
    5. 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.)
    6. 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
    7. 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
    8. 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)
    9. Participation in prior investigational study within 30 d prior to enrollment or within 5-half-lives of the investigational product, whichever is longer
    10. 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.5.1Primary end point(s)
    Incidence of AEs, Grade 3/4 AEs & SAEs during treatment with ribociclib + letrozole
    E.5.1.1Timepoint(s) of evaluation of this end point
    refer to section 10.4. of the protocol
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Patient Reported Outcome (PRO)
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA300
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Hong Kong
    Russian Federation
    Saudi Arabia
    United Arab Emirates
    United Kingdom
    United States
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1200
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2000
    F.4.2.2In the whole clinical trial 3246
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    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 and continue to receive the drugs until progression, intolerance, death or physician/patient decision, but only safety and clinical benefit as assessed by investigator will be collected during the Extension Phase. The duration of the extension phase will be addressed
    in a future amendment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-02-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-12-03
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