ABCSG 46/CompLEEment-1 Details
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 receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease.
- Sample size:
- 3.000 (international), 30 (national)
Primary Objective(s) and Key Secondary 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.
- 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.
- 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.
- 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.
- Male or female with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
- 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.
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.
Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure menopausal status.
Premenopausal status is defined as either:
Patient had last menstrual period within the last 12 months
OR 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 In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.
Perimenopausal status is define as neither premenopausal nor postmenopausal.
Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer 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.
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
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 < 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
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
Patient must be able to swallow ribociclib and letrozole tablets.
Patient has signed informed consent obtained before any trial-related activities and according to local guidelines.
Patients must be able to communicate with the investigator and comply with the requirements of the study procedures.
- Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole.
- Patient who received any CDK4/6 inhibitor.
- 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.
● Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior neo (adjuvant) therapy 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 entry .
- 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 side effects.
- 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).
- 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% of the bone marrow was irradiated.
- 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.
- 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.
- 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)
- Patient has a known history of HIV infection (testing not mandatory)
- 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.)
- 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, or any of the following:
i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
ii. Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication
iii. Inability to determine the QTcF (Fridericia’s correction) interval on screening
● Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening
- 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.
- 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.
Participation in a prior investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer.
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
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 (no sexual relations), when this is in line with the preferred and usual lifestyle. Periodic abstinence like calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal are not acceptable methods of contraception.
Total hysterectomy (surgical removal of the uterus and cervix) or tubal ligation (getting the “tubes tied”) at least 6 weeks before taking study treatment.
The male partner has already been sterilized (at least 6 months prior to screening) with the appropriate documentation. The sterilized male partner should be the sole partner.
Use of a combination of the following:
Placement of an intrauterine device (IUD) or intrauterine system (IUS), and
Use of an occlusive cap (diaphragm or cervical/vault cap) by female, or a condom by the male partner combined with a spermicidal foam/gel/film/cream/vaginal suppository.