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A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer (MONARCH 3)

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ClinicalTrials.gov Identifier: NCT02246621
Recruitment Status : Active, not recruiting
First Posted : September 23, 2014
Results First Posted : March 23, 2018
Last Update Posted : September 10, 2019
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Tracking Information
First Submitted Date  ICMJE September 18, 2014
First Posted Date  ICMJE September 23, 2014
Results First Submitted Date  ICMJE January 31, 2018
Results First Posted Date  ICMJE March 23, 2018
Last Update Posted Date September 10, 2019
Actual Study Start Date  ICMJE November 6, 2014
Actual Primary Completion Date January 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 19, 2018)
Progression Free Survival (PFS) [ Time Frame: Randomization to Progressive Disease or Death Due to Any Cause (Up to 26 Months) ]
PFS defined as the time from the first day of therapy to the first evidence of disease progression as defined by RECIST v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
Original Primary Outcome Measures  ICMJE
 (submitted: September 18, 2014)
Progression Free Survival (PFS) [ Time Frame: Baseline up to Measured Progressive Disease or Death from Any Cause (Approximately 34 Months) ]
Change History Complete list of historical versions of study NCT02246621 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 19, 2018)
  • Overall Survival (OS) [ Time Frame: Randomization to Progressive Disease or Death Due to Any Cause (Estimated Up to 82 Months) ]
    OS defined as the time from first dose date to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.
  • Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) [ Time Frame: Randomization to Progressive Disease or Death Due to Any Cause (Up to 26 Months) ]
    ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions.
  • Duration of Response (DoR) [ Time Frame: CR or PR to Disease Progression or Death Due to Any Cause (Up to 26 Months) ]
    DOR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date.
  • Percentage of Participants With CR, PR or Stable Disease (SD) (Disease Control Rate [DCR]) [ Time Frame: Randomization to Progressive Disease or Death Due to Any Cause (Up to 26 Months) ]
    DCR was the percentage of participants with a best overall response of CR, PR, or SD as per response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions.
  • Percentage of Participants With Tumor Response of SD for at Least 6 Months, PR, or CR (Clinical Benefit Rate [CBR]) [ Time Frame: Randomization to Progressive Disease or Death Due to Any Cause (Up to 26 Months) ]
    CBR defined as percentage of participants with best overall response of CR, PR, or SD with a duration of at least 6 months. CR, PR, or SD were defined using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. Percentage of participants = (participants with CR+PR+SD with a duration of at least 6 months / number of participants enrolled) * 100.
  • Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores [ Time Frame: Baseline, End of Study (Estimated up to 34 Months) ]
    EORTC QLQ-C30 v3.0 is a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. Functional scale options are defined on a 7-point scale ranging from 1, "Very poor" to 7, "Excellent". A linear transformation is applied to standardize the raw scores to range between 0 and 100. For functional domains and global health status, higher scores represent a better level of functioning. Best change from baseline results determined by Least Square (LS) mean estimated with randomization stratification factors and baseline value as continuous covariate. EORTC change score definitions are described in Cocks et al, (2012) and differ for each item. Small changes are generally defined as at least a 3, 4 or 5 point change from baseline.
  • Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores [ Time Frame: Baseline, End of Study (Estimated up to 34 Months) ]
    EORTC QLQ-C30 v3.0 is a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. Symptom scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For symptoms scales, higher scores represented a greater degree of symptoms. Best change from baseline results determined by Least Square (LS) mean estimated with randomization stratification factors and baseline value as continuous covariate. EORTC change score definitions are described in Cocks et al, (2012) and differ according to each item. Small changes are generally defined as at least a 3, 4 or 5 point change from baseline
  • Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire [ Time Frame: Baseline, End of Study (Estimated up to 34 Months) ]
    The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much" . All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning.
  • Change From Baseline to End of Study in Health Status on the EuroQuol 5-Dimension 5 Level (EuroQol-5D 5L) [ Time Frame: Baseline, End of Study (Estimated up to 34 Months) ]
    The EuroQol-5D (version 5L) is a brief self-administered, validated instrument consisting of 2 parts.The first part consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/ depression); a participant is asked to rate each state on a five level scale (no problem, slight problem, moderate problem, severe problem and extreme problem) with higher levels indicating greater severity/ impairment. Published weights are available that allow for the creation of a single summary score called the EQ-5D index that ranges from 0 to 1, with low scores representing a higher level of dysfunction and 1 as perfect health. Minimally important differences in the EQ-5D index score are 0.06 or greater in cancer patients, per Pickard et al (2007).
  • Change From Baseline to End of Study in Health Status on the EuroQol-5D 5L Visual Analog Scale (VAS) Scores Scale [ Time Frame: Baseline, End of Study (Estimated up to 34 Months) ]
    The EuroQol-5D (version 5L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). Minimally important differences in the EQ-5D VAS score are 7 or greater in cancer patients, per Pickard et al (2007).
  • Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Abemaciclib and Its Metabolites M2 and M20 [ Time Frame: Cycle 1 Day 1; 2 to 4 hours (h) post dose, Cycle 2 Day 1; 3 h post dose; 7 h post dose, Cycle 3 Day 1; pre dose, 3 h post dose ]
  • PK: Hepatic Clearance of Abemaciclib, and Apparent Hepatic Clearance of Its Metabolites M2 and M20 [ Time Frame: Cycle 1 Day 1; 2 to 4 hours (h) post dose, Cycle 2 Day 1; 3 h post dose; 7 h post dose, Cycle 3 Day 1; pre dose, 3 h post dose ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 18, 2014)
  • Overall Survival (OS) [ Time Frame: Baseline to Date of Death from Any Cause (Approximately 82 Months) ]
  • Duration of Response (DoR) [ Time Frame: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 34 Months) ]
  • Disease Control Rate (DCR) [ Time Frame: Baseline to Disease Progression (Approximately 34 Months) ]
  • Clinical Benefit Rate (CBR) [ Time Frame: Baseline to Disease Progression (Approximately 34 Months) ]
  • Change from Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [ Time Frame: Baseline, End of Study (up to 34 Months) ]
  • Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire [ Time Frame: Baseline, End of Study (up to 34 Months) ]
  • Change from Baseline to End of Study in Health Status on the EuroQuol 5-Dimension 5 Level (EuroQol-5D 5L) [ Time Frame: Baseline, End of Study (up to 34 Months) ]
  • Pharmacokinetics (PK): Volume of Distribution of LY2835219, its Metabolites, and NSAI Therapy [ Time Frame: Cycle 1 Postdose through Cycle 4 (Approximately 4 Months) ]
  • Objective Response Rate (ORR) [ Time Frame: Baseline to Disease Progression (Approximately 34 Months) ]
  • PK: Clearance of LY2835219, its Metabolites, and NSAI Therapy [ Time Frame: Cyle 1 Postdose through Cycle 4 (Approximately 4 Months) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer
Official Title  ICMJE A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) Plus LY2835219, a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer With No Prior Systemic Therapy in This Disease Setting
Brief Summary The main purpose of this study is to evaluate how effective nonsteroidal aromatase inhibitors (NSAI) plus abemaciclib are in postmenopausal women with breast cancer. Participants will be randomized to abemaciclib or placebo in a 2:1 ratio.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Abemaciclib
    Administered orally
    Other Name: LY2835219
  • Drug: Anastrozole
    Administered orally
  • Drug: Letrozole
    Administered orally
  • Drug: Placebo
    Administered orally
Study Arms  ICMJE
  • Experimental: Abemaciclib + NSAI
    150 milligrams (mg) Abemaciclib orally every 12 hours plus either 1 mg anastrozole or 2.5 mg letrozole orally once daily for 28 days (28 day cycles).
    Interventions:
    • Drug: Abemaciclib
    • Drug: Anastrozole
    • Drug: Letrozole
  • Placebo Comparator: Placebo + NSAI
    Placebo orally every 12 hours plus either 1 mg anastrozole or 2.5 mg letrozole orally once daily for 28 days (28 day cycles).
    Interventions:
    • Drug: Anastrozole
    • Drug: Letrozole
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 19, 2018)
493
Original Estimated Enrollment  ICMJE
 (submitted: September 18, 2014)
450
Estimated Study Completion Date  ICMJE July 12, 2021
Actual Primary Completion Date January 31, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Have a diagnosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer
  • Have locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease
  • Have postmenopausal status
  • Have either measurable disease or nonmeasurable bone-only disease
  • Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale
  • Have adequate organ function
  • Have discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture prior to randomization and recovered from the acute effects of therapy
  • Are able to swallow capsules

Exclusion Criteria:

  • Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis
  • Have inflammatory breast cancer
  • Have clinical evidence or a history of central nervous system (CNS) metastasis
  • Are currently receiving or have previously received endocrine therapy for locoregionally recurrent or metastatic breast cancer
  • Have received prior (neo)adjuvant endocrine therapy with a disease-free interval ≤12 months from completion of treatment
  • Are currently receiving or have previously received chemotherapy for locoregionally recurrent or metastatic breast cancer
  • Have received prior treatment with everolimus
  • Have received prior treatment with any cyclin-dependent kinase (CDK) 4/6 inhibitor (or participated in any CDK4/6 inhibitor clinical trial for which treatment assignment is still blinded)
  • Have initiated bisphosphonates or approved receptor activator of nuclear factor kappa-B ligand (RANK-L) targeted agents <7 days prior to randomization
  • Are currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study
  • Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of randomization for a nonmyelosuppressive or myelosuppressive agent, respectively
  • Have had major surgery within 14 days prior to randomization
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Mexico,   Australia,   Austria,   Belgium,   Canada,   France,   Germany,   Greece,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   New Zealand,   Puerto Rico,   Russian Federation,   Slovakia,   Spain,   Sweden,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02246621
Other Study ID Numbers  ICMJE 15417
I3Y-MC-JPBM ( Other Identifier: Eli Lilly and Company )
2014-001502-18 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting
Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
URL: https://vivli.org/
Responsible Party Eli Lilly and Company
Study Sponsor  ICMJE Eli Lilly and Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
PRS Account Eli Lilly and Company
Verification Date August 1, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP