safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre / postmenopausal women with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease

• Register: EUCTR
• Last refreshed on: 11 March 2020
• Main ID: EUCTR2016-003467-19-GB
• Date of registration: 07/11/2016
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma AG
• Public title: safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre / postmenopausal women with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
• Scientific title: 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
• Date of first enrolment: 15/12/2016
• Target sample size: 3000
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003467-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Austria, Belgium, Bulgaria, Canada, Chile, Czech Republic, Denmark, Egypt, Finland, France, Greece, Hong Kong, Hungary, India, Israel, Italy, Jordan, Lebanon, Luxembourg, Malaysia, Mexico, Netherlands, Norway, Oman, Panama, Philippines, Poland, Portugal, Russian Federation, Saudi Arabia, Singapore, Slovakia, Slovenia, Spain, Sweden, Taiwan, Thailand, United Arab Emirates, United Kingdom, United States

Contacts

• Name: Medica Information Services
• Affiliation: Novartis Pharmaceuticals UK Limited

• Name: Medica Information Services
• Affiliation: Novartis Pharmaceuticals UK Limited

Key inclusion & exclusion criteria

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 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 andnplasma 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.
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 w
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 CYP

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
MedDRA version: 21.1 Level: LLT Classification code 10072737 Term: Advanced breast cancer System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Kisqali
Product Name: ribociclib
Product Code: LEE011
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: RIBOCICLIB
CAS Number: 1374639-75-4
Current Sponsor code: LEE011
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Secondary Objective: • 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

Main Objective: 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

Primary end point(s): Incidence of AEs, Grade 3/4 AEs & SAEs during treatment with ribociclib + letrozole

Timepoint(s) of evaluation of this end point: refer to section 10.4. of the protocol

Secondary Outcome(s)

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

Timepoint(s) of evaluation of this end point: refer to section 10.5.1 of the protocol

Secondary ID(s)

2016-003467-19-BE

CLEE011A2404

Source(s) of Monetary Support

Novartis Pharma AG

Ethics review

Status: Approved
Approval date: 10/11/2016
Contact: