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

Phase 3

Completed

Conditions: Breast Cancer

Interventions: Drug: Ribociclib
Drug: Letrozole
Drug: Goserelin
Drug: Leuprolide

Registration Number: NCT02941926

Lead Sponsor: Novartis Pharmaceuticals

Brief 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..

Detailed Description: This was an open-label, single arm, multi-center Phase IIIb study. The study was composed of 2 phases: Core Phase and Extension Phase. In the Core Phase, safety and efficacy data was collected. The study treatment during the Core Phase was provided until disease progression, death, unacceptable toxicities, physician's decision, subject/guardian's decision, protocol deviation, study termination by sponsor, lost to follow-up, technical problems or up to 18 months after LPFV.

In the event that patients were still deriving benefit at the end of the Core phase and ribociclib was not approved or available and reimbursed, patients were transitioned to the Extension Phase and continued to receive study treatment until progression, intolerance, death or physician/patient decision. Only safety and clinical benefit (as assessed by investigator) data was collected in the Extension Phase. During the Extension Phase, if ribociclib became locally approved and reimbursed, patients were to be transitioned to prescription. Patients who completed the Extension Phase and continued to derive clinical benefit from the treatment based on the investigator's evaluation received ribociclib from prescription (if approved and reimbursed), another post-trial access program, or other drug access/support program(s).

Canadian sub-study: this sub-study was a multicenter Canadian exploratory correlative sample collection sub-study that aimed to better understand mechanisms of response and resistance to ribociclib in combination with letrozole therapy. This sub-study was available for all Canadian subjects enrolled on the main study and did not alter the planned treatment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3246

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ribociclib + letrozole+goserelin/leuprolide	Ribociclib	Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Ribociclib + letrozole+goserelin/leuprolide	Goserelin	Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Ribociclib + letrozole+goserelin/leuprolide	Letrozole	Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Ribociclib + letrozole+goserelin/leuprolide	Leuprolide	Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase	From start of treatment up to 30 days after last treatment (for participants who did not enter to the Extension phase) or up to last treatment in the Core phase (for participants who entered the Extension phase), assessed up to approximately 33 months.	AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. A SAE which caused death of the participant was considered as fatal SAE. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.

Secondary Outcome Measures

Name	Time	Method
Time-to-Progression (TTP) Based on Investigator's Assessment (Core Phase)	Up to approximately 33 months	Time to progression (TTP) is defined as time from date of start of treatment to the date of first documented progression or death due to underlying cancer. Participants with symptoms of rapidly progressing disease without radiologic evidence were classified as progression only when clear evidence of clinical deterioration was documented and/or patient discontinued due to 'Disease progression' or death due to study indication. When there was no documentation of radiologic evidence of progression, and the patient discontinued for 'Disease progression' due to documented clinical deterioration of disease, the date of discontinuation was used as date of progression. TTP was estimated using the Kaplan-Meier method. 95% CI of median was calculated according to Brookmeyer and Crowley method.
Clinical Benefit Rate (CBR) Based on Investigator's Assessment (Core Phase)	Up to approximately 33 months	Clinical benefit rate (CBR) is defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1 based on investigator's assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. 95% CI was calculated using the exact binomial method.
Overall Response Rate (ORR) Based on Investigator's Assessment (Core Phase)	Up to approximately 33 months	Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. 95% CI was calculated using the exact binomial method.
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase)	On Day 1 of Cycle 1, 2, 3, 4 ,5, 6, 8, 10, 12 and after that every 3 cycles, and End of treatment, assessed up to 33 months. Cycle=28 days	Change from baseline in FACT-B scores was assessed. FACT-B is a self-report instrument that measures multidimensional quality of life (QOL) in patients with breast cancer. The FACT-B consists of 37 questions that address physical, social, emotional, and functional well-being, with specific questions relevant to women with breast cancer. Each item has a score range of 0 (Not at all) to 4 (Very much), with a total score ranging from 0-148. The higher the score, the better the QOL reported by the participant. A positive change from baseline indicates improvement in QoL. Due to the nature of the questionnaire, only females were asked to complete this questionnaire.
Number of Participants With AEs and SAEs in the Extension Phase	From first dose of treatment in the Extension phase up to 30 days after last dose of treatment, assessed up approximately 37.6 months	AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.
Number of Participants With Clinical Benefit (Extension Phase)	On Day 1 of every 3 cycles, starting from Cycle 1 of the Extension phase until end of treatment, assessed up to 37.4 months. Cycle= 28 days	Clinical benefit as assessed by the Investigator during Extension phase

Trial Locations

Locations (72): Ventura County Hematology and Oncology
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Oxnard, California, United States
Mid Florida Hematology and Onc Ctr
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Orange, Florida, United States
Hope Cancer Center of East Texas
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Tyler, Texas, United States
Northern Light Mercy Hospital SC
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Portland, Maine, United States
Cheyenne Regional Medical Center Cheyenne Regional Med Ctr (3)
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Cheyenne, Wyoming, United States
Novartis Investigative Site
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Stoke-on-Trent, United Kingdom
Kaiser Permanente
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Rockville, Maryland, United States
Alpha Med Physician Group, LLC
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Tinley Park, Illinois, United States
Cleveland Clinic Foundation Cleveland Clinic (5)
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Cleveland, Ohio, United States
Millennium Research Clin Develop Millennium Oncology - FL
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Houston, Texas, United States
The Christ Hospital Cancer Center Research Program Linder Research Center
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Cincinnati, Ohio, United States
Alaska Cancer Research and Education Center
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Anchorage, Alaska, United States
Foundation for Sickle Cell Disease Research
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Hollywood, Florida, United States
Joliet Oncology-Hematology Associates Presence Cancer Center
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Joliet, Illinois, United States
University of Kansas Medical Center University of Kansas Med Ctr 9
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Kansas City, Kansas, United States
Jackson Oncology Associates
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Jackson, Mississippi, United States
Poudre Valley Hospital Poudre Valley Health System
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Fort Collins, Colorado, United States
Valley View Hospital Cancer Center
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Glenwood Springs, Colorado, United States
Sarah Cannon at Overland Park Regional Medical Center
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Overland Park, Kansas, United States
Mays Cancer Ctr Uthsa Mdacc
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San Antonio, Texas, United States
California Pacific Medical Center Onc Dept
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San Francisco, California, United States
Arizona Oncology Associates
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Phoenix, Arizona, United States
Beverly Hills Cancer Center
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Beverly Hills, California, United States
Pacific Shores Medical Group SC
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Long Beach, California, United States
USC Norris Cancer Center
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Los Angeles, California, United States
University of California Irvine UC Irvine (11)
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Orange, California, United States
PCR Oncology
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Pismo Beach, California, United States
John D Archbold Memorial Hospital John D. Archbold Mem Hosp (4)
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Thomasville, Georgia, United States
Summit Cancer Care Summit Cancer Care (SC)
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Savannah, Georgia, United States
Mid Illinois Hematology Oncology Mid Illinois Hema/Onc (3)
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Normal, Illinois, United States
Stroger Cook County Hospital Division of Hematology & Onc
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Chicago, Illinois, United States
June E. Nylan Cancer Center
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Sioux City, Iowa, United States
New Mexico Cancer Care Alliance .
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Albuquerque, New Mexico, United States
Indian Univ Health Goshen Center forCancer SC
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Goshen, Indiana, United States
Northwest Oncology
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Munster, Indiana, United States
San Juan Oncology Associates
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Farmington, New Mexico, United States
Eastchester Center for Cancer Care
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Bronx, New York, United States
Clinical Research Alliance
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Lake Success, New York, United States
University Hospitals of Cleveland Seidman Cancer Center Cleveland Medical Center
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Cleveland, Ohio, United States
Oncology Speciialists of Charlotte
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Charlotte, North Carolina, United States
Oklahoma Cancer Specialists and Research Institute SC-2
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Tulsa, Oklahoma, United States
Aultman Cancer Center Main Centre
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Canton, Ohio, United States
Dayton Physicians
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Kettering, Ohio, United States
Virginia Oncology Associates
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Norfolk, Virginia, United States
PeaceHealth St Joseph Medical Center
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Bellingham, Washington, United States
Providence Regional Medical Centre of Everett
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Everett, Washington, United States
Virginia Mason Medical Center-Oncology SC
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Seattle, Washington, United States
Kadlec Clinic Hematology and Onco
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Kennewick, Washington, United States
Valley Medical Center Research Valley Medical Center
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Renton, Washington, United States
Northwest Medical Specialties Dept.ofNW Med. Specialties
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Tacoma, Washington, United States
Medical Faculty Assc Inc Medical Faculty Assc., Inc. (2
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Washington DC, Maryland, United States
Florida Cancer Research Institute Dept of Oncology
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Davie, Florida, United States
Englewood Health
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Englewood, New Jersey, United States
Greater Baltimore Medical Center Cancer Center Greater Baltimore Medical Ctr
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Baltimore, Maryland, United States
The Valley Hospital / Luckow Pavillion
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Paramus, New Jersey, United States
Watson Clinic Center for Research 1730 Location
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Lakeland, Florida, United States
Highlands Oncology Group
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Fayetteville, Arkansas, United States
Nebraska Hematology-Oncology, P.C.
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Lincoln, Nebraska, United States
Saint Alphonsus Regional Medical Center
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Boise, Idaho, United States
Somerset Hematology Oncology Associates Somerset Hematolgy Onc -MI
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Somerset, New Jersey, United States
Comprehensive Cancer Centers of Nevada CCC of Nevada Henderson (4)
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Henderson, Nevada, United States
McLeod Center for Cancer Treatment and Research
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Florence, South Carolina, United States
Maryland Oncology Hematology P A Columbia
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Rockville, Maryland, United States
Carolina Blood and Cancer Care of South Carolina
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Rock Hill, South Carolina, United States
Centura Health Research Center Centura Health Research Center
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Denver, Colorado, United States
Nebraska Cancer Specialists Oncology Hematology West
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Omaha, Nebraska, United States
Oregon Health Sciences University SC-5
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Portland, Oregon, United States
Columbia St Mary s Hospital of Milwaukee St. Mary's Hospital Ozaukee
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Milwaukee, Wisconsin, United States
John Ochsner Heart and Vascular Institute Clinical Trials
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New Orleans, Louisiana, United States
Arizona Oncology Associates Arizona Oncology Assoc. (2)
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Tucson, Arizona, United States
Ironwood Cancer and Research Centers
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Chandler, Arizona, United States
Trinitas Comprehensive Cancer Center
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Elizabeth, New Jersey, United States