Study to Assess the Safety and Efficacy of Ribociclib (LEE011) in Combination With Letrozole for the Treatment of Men and Pre/Postmenopausal Women With HR+ HER2- aBC
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Ribociclib; Letrozole; Goserelin; Leuprolide
Intervention description: Ribociclib was centrally supplied to the investigators and administered orally once a day on days 1-21 of each 28 day cycle at a starting dose of 600 mg daily; Letrozole was procured locally and administered orally once a day on a continuous daily schedule at a dose of 2.5 mg; Goserelin was procured locally and administered in men and premenopausal women as an injectable subcutaneous implant administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 3.6 mg (cycle = 28 days); Leuprolide was procured locally and administered in men and premenopausal women as an injectable intramuscular depot administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 7.5 mg (cycle= 28 days)
Intervention MeSH terms: Letrozole; Leuprolide; Goserelin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3246.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HR-positive HER2-negative; advanced breast cancer; LEE011; ribociclib; letrozole; goserelin; CDK; CDK4; CDK6; CDK4/6; Phase IIIb; ER-positive; PR-positive; premenopausal; postmenopausal; men with advanced breast cancer

Summary:

      The purpose of this study is to collect additional safety and efficacy data for the
      combination of ribociclib + letrozole in men and pre/postmenopausal women with HR+HER2-
      advanced breast cancer and no prior hormonal treatment for advanced disease..
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Male or female advanced (locoregionally recurrent or metastatic) breast cancer not
             amenable to curative therapy.

          -  In the case of women, both pre/perimenopausal and postmenopausal patients were allowed
             to be included in this study; menopausal status was relevant for the requirement of
             goserelin to be used concomitantly with ribociclib and letrozole.

               1. Postmenopausal status was defined either by: I).Prior bilateral oophorectomy OR
                  ii). Age ≥ 60 OR iii). 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 was
                  taking tamoxifen or toremifene and age < 60, then FSH and plasma estradiol levels
                  would be in post-menopausal range per local normal range (NCCN Guidelines version
                  2.2017).

                  Note: For women with therapy-induced amenorrhea, serial measurements of FSH
                  and/or estradiol were needed to ensure menopausal status.

               2. Premenopausal status was 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.

               3. Perimenopausal status was define as neither premenopausal nor postmenopausal

          -  Patient had a histologically and/or cytologically confirmed diagnosis of
             estrogen-receptor positive and/or progesterone receptor positive breast cancer by
             local laboratory.

          -  Patient had 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 was required by local laboratory testing.

          -  Patient had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2

          -  Patient had 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 × 10^9/L

               -  Platelets ≥ 100 × 10^9/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 had 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 had 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

        Key Exclusion Criteria:

          -  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
             was permitted. Note:

               -  Patients who received (neo) adjuvant therapy for breast cancer were eligible. If
                  the prior neo (adjuvant) therapy included letrozole or anastrozole the disease
                  free interval had to 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 were eligible.

               -  Any prior (neo) adjuvant anti-cancer therapy or prior chemotherapy for metastatic
                  disease had to be stopped at least 5 half-lives or 7 days, whichever was longer,
                  before study inclusion.

          -  Patient was concurrently using other anti-cancer therapy.