A Study of Abemaciclib (LY2835219) in Women With HR+, HER2+ Locally Advanced or Metastatic Breast Cancer (monarcHER)

• ClinicalTrials.gov Identifier: NCT02675231
• Recruitment Status: Completed
• First Posted: February 5, 2016
• Results First Posted: May 26, 2020
• Last Update Posted: March 19, 2024
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: February 3, 2016
• First Posted Date: February 5, 2016
• Results First Submitted Date: April 8, 2020
• Results First Posted Date: May 26, 2020
• Last Update Posted Date: March 19, 2024
• Actual Study Start Date: May 23, 2016
• Actual Primary Completion Date: April 8, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2020)

Progression Free Survival (PFS) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Up To 36 Months) ]

PFS time was measured from the date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, 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 first dose, 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 (submitted: February 3, 2016): Progression Free Survival (PFS) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Estimated up to 24 Months) ]

Current Secondary Outcome Measures (submitted: May 15, 2020)

• Overall Survival (OS) [ Time Frame: Baseline to Death from Any Cause (Estimated up to 48 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 Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: Baseline to Objective Disease Progression (Up To 36 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: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Up To 36 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 a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) [ Time Frame: Baseline to Objective Disease Progression (Up To 36 Months) ]
  Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (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 Best Overall Response of CR, PR, or SD With Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR) [ Time Frame: Date of CR, PR or SD to 6 Months Post CR, PR or SD (Up To 36 Months) ]
  Clinical benefit rate 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 in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf) [ Time Frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) ]
  The mBPI-sf is an 11-item instrument used as a multiple-item measure of cancer pain intensity. In addition to pain intensity (4 items), the mBPI-sf is designed for participants to record the presence of pain in general, pain relief, and pain interference with function (general activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, enjoyment of life). Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales anchored at 0 (no pain or does not interfere) and 10 (pain as bad as you can imagine or completely interferes). The mBPI-sf recall period is 24 hours and typical completion time for this instrument is less than 5 minutes. Mean Interference Score data is reported here. Least square (LS) Mean value was controlled for Treatment, visit, Treatment*Visit and baseline.
• Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [ Time Frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) ]
  EORTC QLQ-C30 v3.0 was 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. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For functional domains and global health status, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline.
• Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [ Time Frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) ]
  The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Participants completed the 5-level (no problem, slight problem, moderate problem, severe problem, and inability or extreme problem), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. Five dimensions of health status are each assessed with 5 response options and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status.LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline.
• Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) [ Time Frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) ]
  European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) is a standardized measure of health status of the participant. The EQ-5D-5L is assessed using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. A higher score indicates better health state. LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline.
• Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) [ Time Frame: Cycle(C)1 Day(D)1,C1D15, C2D1, C2D8, C3D1,C3D15, C4D1, C5D1:pre-dose; C1D1, C2D1, C3D1, C4D1, C5D1:post-dose ]
  Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) was evaluated. M2 and M20 are 2 major active metabolites of abemaciclib.

Original Secondary Outcome Measures (submitted: February 3, 2016)

• Overall Survival (OS) [ Time Frame: Baseline to Death from Any Cause (Estimated up to 48 Months) ]
• Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: Baseline to Objective Disease Progression (Estimated up to 24 Months) ]
• Duration of Response (DoR) [ Time Frame: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Estimated up to 24 Months) ]
• Percentage of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) [ Time Frame: Baseline to Objective Disease Progression (Estimated up to 24 Months) ]
• Proportion of Participants with Best Overall Response of CR, PR, or SD with Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR) [ Time Frame: Date of CR, PR or SD to 6 Months Post CR, PR or SD (Estimated up to 24 Months) ]
• Change from Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf) [ Time Frame: Baseline, up to 30 Days After Treatment Discontinuation (Estimated up to 24 Months) ]
• Change from Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [ Time Frame: Baseline, up to 30 Days After Treatment Discontinuation (Estimated up to 24 Months) ]
• Change from Baseline in Health Status on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) [ Time Frame: Baseline, up to 30 Days After Treatment Discontinuation (Estimated up to 24 Months) ]
• Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and its Metabolites, Fulvestrant, and Trastuzumab [ Time Frame: Predose Cycle 1 through Cycle 5 Day 1 (Approximately 4 Months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Abemaciclib (LY2835219) in Women With HR+, HER2+ Locally Advanced or Metastatic Breast Cancer
• Official Title: monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of Abemaciclib Plus Trastuzumab With or Without Fulvestrant to Standard-of-Care Chemotherapy of Physician's Choice Plus Trastuzumab in Women With HR+, HER2+ Locally Advanced or Metastatic Breast Cancer
• Brief Summary: The purpose of this study is to evaluate the effectiveness of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus physicians choice standard of care chemotherapy in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) locally advanced or metastatic breast cancer after prior exposure to at least two HER2-directed therapies for advanced disease.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hormone Receptor Positive Breast Cancer
• HER-2 Positive Breast Cancer

Intervention

• Drug: Abemaciclib
  Administered Orally
  Other Name: LY2835219
• Drug: Trastuzumab
  Administered IV
• Drug: Fulvestrant
  Administered IM
• Drug: Standard of Care Single Agent Chemotherapy
  Standard-of-care single-agent chemotherapy of physician's choice administered according to product label

Study Arms

• Experimental: 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
  150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.
  Interventions:

  • Drug: Abemaciclib
  • Drug: Trastuzumab
  • Drug: Fulvestrant
• Experimental: 150 mg Abemaciclib + 8 mg/kg Trastuzumab
  150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.
  Interventions:

  • Drug: Abemaciclib
  • Drug: Trastuzumab
• Active Comparator: 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
  8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician's choice administered according to product label
  Interventions:

  • Drug: Trastuzumab
  • Drug: Standard of Care Single Agent Chemotherapy

• Publications *: Tolaney SM, Wardley AM, Zambelli S, Hilton JF, Troso-Sandoval TA, Ricci F, Im SA, Kim SB, Johnston SR, Chan A, Goel S, Catron K, Chapman SC, Price GL, Yang Z, Gainford MC, Andre F. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020 Jun;21(6):763-775. doi: 10.1016/S1470-2045(20)30112-1. Epub 2020 Apr 27. Erratum In: Lancet Oncol. 2021 Mar;22(3):e92. Lancet Oncol. 2021 Nov;22(11):e472.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 15, 2020): 237
• Original Estimated Enrollment (submitted: February 3, 2016): 225
• Actual Study Completion Date: November 9, 2023
• Actual Primary Completion Date: April 8, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• diagnosis of HR+, HER2+ breast cancer (BC)
• unresectable locally advanced recurrent BC or metastatic BC
• adequate tumor tissue available prior to randomization
• measurable and/or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

• previously received:

  • at least 2 HER2-directed therapies for advanced disease
  • participant must have received trastuzumab emtansine (T-DM1) in any disease setting
• must have received a taxane in any disease setting
• may have received any endocrine therapy (excluding fulvestrant)
• have postmenopausal status due to surgical / natural menopause or chemical ovarian suppression
• performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology Group scale
• left ventricular ejection fraction (LVEF) of 50% or higher at baseline
• adequate organ function
• negative serum pregnancy test at baseline (within 14 days prior to randomization) and agree to use medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of abemaciclib if menopause induced by gonadotropin-releasing hormone (GnRH) agonist or radiation
• discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture at least 2 weeks prior to randomization and recovered from the acute effects of therapy
• discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and endocrine therapy), except trastuzumab, for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy
• are able to swallow capsules

Exclusion Criteria:

• have visceral crisis
• known central nervous system (CNS) metastases that are untreated, symptomatic, or require steroids to control symptoms
• had major surgery within 14 days prior to randomization
• received prior treatment with any cyclin-dependent kinase (CDK) 4 and CDK 6 inhibitor
• 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 serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study
• history within the last 6 months of symptomatic congestive heart failure, myocardial infarction, or unstable angina
• history within the last 12 months of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest
• history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years
• active bacterial, fungal infection, or detectable viral infection
• have received any recent (within 28 days prior to randomization) live virus vaccination
• hypersensitivity to trastuzumab, murine proteins, fulvestrant, or to any of the excipients

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, France, Germany, Greece, Italy, Korea, Republic of, Mexico, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02675231
• Other Study ID Numbers: 15804; I3Y-MC-JPBZ ( Other Identifier: Eli Lilly and Company ); 2015-003400-24 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• 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 european union (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/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• 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: March 2024