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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 (COMPLEEMENT-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02941926
Recruitment Status : Active, not recruiting
First Posted : October 21, 2016
Results First Posted : May 9, 2022
Last Update Posted : May 9, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( 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..

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Ribociclib Drug: Letrozole Drug: Goserelin Drug: Leuprolide Phase 3

Detailed Description:

This is an open-label, single arm, multi-center Phase IIIb study. The study is 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. The extension phase is still on-going, and results of the extension phase will be provided after study completion.

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 will continue to receive study treatment until progression, intolerance, death or physician/patient decision. Only safety and clinical benefit (as assessed by investigator) data will be collected in the Extension Phase. During the Extension Phase, if ribociclib is approved and reimbursed, patients will be transitioned to prescription or drug access/support program(s) according to local laws and regulations. The Extension Phase is ongoing.

Canadian sub-study: this sub-study is a multicenter Canadian exploratory correlative sample collection sub-study that aims 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3246 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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 Receptor-positive (HR+) HER2-negative (HER2-) Advanced Breast Cancer (aBC) With no Prior Hormonal Therapy for Advanced Disease
Actual Study Start Date : November 30, 2016
Actual Primary Completion Date : November 8, 2019
Estimated Study Completion Date : September 5, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Ribociclib + letrozole+goserelin/leuprolide
Participants will 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 will be given as an injectable subcutaneous implant or leuprolide will be given as an intramuscular injection.
Drug: Ribociclib
Ribociclib is 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
Other Name: LEE011

Drug: Letrozole
Letrozole is procured locally and administered orally once a day on a continuous daily schedule at a dose of 2.5 mg

Drug: Goserelin
Goserelin is 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)

Drug: Leuprolide
Leuprolide is 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)




Primary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase [ Time Frame: 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 :
  1. Time-to-Progression (TTP) Based on Investigator's Assessment (Core Phase) [ Time Frame: 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.


  2. Overall Response Rate (ORR) Based on Investigator's Assessment (Core Phase) [ Time Frame: 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.


  3. Clinical Benefit Rate (CBR) Based on Investigator's Assessment (Core Phase) [ Time Frame: 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.


  4. Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) [ Time Frame: 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.


  5. Number of Participants With AEs and SAEs in the Extension Phase [ Time Frame: From end of core phase up to approximately 18 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.


  6. Percentage of Participants With Clinical Benefit (Extension Phase) [ Time Frame: From end of core phase up to approximately 18 months ]
    Clinical benefit as assessed by the Investigator


Other Outcome Measures:
  1. Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole [ Time Frame: Screening (up to 28 days before first dose of study treatment) ]
    Exploratory analysis performed in archival tumor samples collected during screening in the main study. Protein expression levels of the ribociclib plus letrozole cohort that did not achieve clinical benefit (progression within 3 months of treatment) and the cohort sensitive to ribociclib and letrozole (cohort with a time to progression of 22 months or more) were determined using using Single-Pot, Solid-Phase-enhanced, Sample Preparation-Clinical Tissue Proteomics (SP3-CTP). For normalization purposes a pooled internal standard sample, comprised of aliquots of every sample included in the study, was included in each experimental batch. Protein abundances were calculated as the log2 transformed abundances relative to the pooled internal standard. Positive values represent higher protein expression levels compared to the pooled internal standard. Expression levels of proteins that showed association to predicting response to study treatment are presented.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.

    1. Postmenopausal status is 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 is taking tamoxifen or toremifene and age < 60, then FSH and plasma estradiol levels should 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 are needed to ensure menopausal status.

    2. 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.

    3. Perimenopausal status is define as neither premenopausal nor postmenopausal Note: Throughout this document, perimenopausal and premenopausal status is grouped together and referred as "Premenopausal"
  • 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 × 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 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

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 is permitted

Note:

  • 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 inclusion.

    • Patient is concurrently using other anti-cancer therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02941926


Locations
Show Show 496 study locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] January 23, 2020
Statistical Analysis Plan  [PDF] December 18, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02941926    
Obsolete Identifiers: NCT03613220
Other Study ID Numbers: CLEE011A2404
2016-003467-19 ( EudraCT Number )
First Posted: October 21, 2016    Key Record Dates
Results First Posted: May 9, 2022
Last Update Posted: May 9, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.


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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Leuprolide
Goserelin
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Antineoplastic Agents, Hormonal