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A Study of Abemaciclib (LY2835219) in Participants With Breast Cancer (MONARCH plus)

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ClinicalTrials.gov Identifier: NCT02763566
Recruitment Status : Active, not recruiting
First Posted : May 5, 2016
Results First Posted : March 30, 2020
Last Update Posted : June 11, 2021
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Brief Summary:
The main purpose of this study is to evaluate the efficacy of the study drug abemaciclib in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) locoregionally recurrent or metastatic breast cancer.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Abemaciclib Drug: Anastrozole Drug: Letrozole Drug: Placebo Drug: Fulvestrant Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 463 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare NSAI (Anastrozole or Letrozole) Plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or Plus Placebo, and to Compare Fulvestrant Plus Abemaciclib or Plus Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer
Actual Study Start Date : December 5, 2016
Actual Primary Completion Date : March 29, 2019
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Abemaciclib + Nonsteroidal Aromatase Inhibitor (NSAI)
Abemaciclib given orally every 12 hours (Q12H) plus anastrozole or letrozole given orally every 24 hours (Q24H) on days 1 to 28 of a 28 day cycle. Participants receiving benefit may continue until disease progression.
Drug: Abemaciclib
Administered orally
Other Name: LY2835219

Drug: Anastrozole
Administered orally

Drug: Letrozole
Administered orally

Experimental: Placebo + NSAI
Placebo given orally Q12H plus anastrozole or letrozole given orally Q24H on days 1 to 28 of a 28 day cycle. Participants receiving benefit may continue until disease progression.
Drug: Anastrozole
Administered orally

Drug: Letrozole
Administered orally

Drug: Placebo
Administered orally

Experimental: Abemaciclib + Fulvestrant
Abemaciclib given orally Q12H on days 1 to 28 of a 28 day cycle plus fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1, then on day 1 of cycle 2 and beyond. Participants receiving benefit may continue until disease progression.
Drug: Abemaciclib
Administered orally
Other Name: LY2835219

Drug: Fulvestrant
Administered intramuscularly

Experimental: Placebo + Fulvestrant
Placebo given orally Q12H on days 1 to 28 of a 28 day cycle plus fulvestrant IM on days 1 and 15 of cycle 1, then on day 1 of cycle 2 and beyond. Participants receiving benefit may continue until disease progression.
Drug: Placebo
Administered orally

Drug: Fulvestrant
Administered intramuscularly




Primary Outcome Measures :
  1. Progression Free Survival (PFS) (Abemaciclib + NSAI & Placebo NSAI) [ Time Frame: Randomization to Measured Progressive Disease or Death (up to 26 Months) ]
    Progression-free survival time was measured from randomization until the date of objective progression as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1), or death from any cause. PD is defined as 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. Patients who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of randomization if no post-baseline radiographic assessment is available.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) (Abemaciclib + Fulvestrant and Placebo + Fulvestrant Arms) [ Time Frame: Randomization to Measured Progressive Disease or Death (up to 26 Months) ]
    Progression-free survival time was measured from randomization until the date of objective progression as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1), or death from any cause. PD is defined as 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. Patients who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of randomization if no post-baseline radiographic assessment is available.

  2. Overall Survival (OS) [ Time Frame: Randomization to Date of Death from Any Cause (Estimated up to 38 Months) ]
  3. Percentage of Participants With Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] [ Time Frame: Randomization to Measured Progressive Disease (up to 26 Months) ]
    Objective response rate is the percentage of participants with a BOR of CR or PR as defined by RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is 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.

  4. Duration of Response (DoR) [ Time Frame: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 38 Months) ]
  5. Percentage of Participants Who Exhibit Stable Disease (SD) or CR or PR [Disease Control Rate (DCR)] [ Time Frame: Randomization to Measured Progressive Disease (up to 26 Months) ]
    Disease control rate (DCR) is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as 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.

  6. 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: Randomization to Measured Progressive Disease (up to 26 Months) ]
    Clinical benefit rate (CBR) is the percentage of participants with a BOR of CR or PR, or SD for at least 6 months. CR is defined as the disappearance of all target and non-target lesions & no appearance of new lesions. PR is 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 is 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. PD is defined as 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.

  7. Change From Randomization in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [ Time Frame: Baseline through 19 Months ]

    consists of 30 items covered by 1 of 3 dimensions:

    1. Global health status/quality of life (2 items) with scores ranging from 1 (Very Poor) to 7 (Excellent).
    2. Functional scales (15 total items addressing either physical, role, emotional, cognitive, or social functioning), each item scores ranging from 1 (not at all) to 4 (very much)
    3. Symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, or financial impact), each item scores ranging from 1 (not at all) to 4 (very much).

    Raw scores are linearly converted to a 0-100 scale with higher scores reflecting higher levels of function/QOL or higher levels of symptom burden.


  8. Pharmacokinetics (PK): Area Under the Concentration Curve of Abemaciclib, Its Metabolites (M2 & M20) [ Time Frame: C1D1 post dose, C2D1 post dose, C3D1 predose, C4D1 predose ]

    Pharmacokinetics (PK): Area Under the Concentration Curve of Abemaciclib and its Metabolites LSN2839567 (M2) & LSN3106726 (M20) was reported.

    C=Cycle, D=day;




Information from the National Library of Medicine

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

Inclusion Criteria:

  • Have a diagnosis of HR+, HER2- breast cancer. Although not required as a protocol procedure, metastatic disease should be considered for biopsy whenever possible to reassess hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status if clinically indicated.

    • To fulfill the requirement for HR+ disease, a breast cancer must express, by immunohistochemistry (IHC), at least 1 of the HRs (estrogen receptor [ER], progesterone receptor [PgR]) as defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.
    • To fulfill the requirement of HER2- disease, a breast cancer must not demonstrate, at initial diagnosis or upon subsequent biopsy, overexpression of HER2 by either IHC or in-situ hybridization as defined in the relevant ASCO/CAP guidelines.
  • Meet either Inclusion Criterion (2a) or Inclusion Criterion (2b). Participants meeting Inclusion Criterion 2a will be enrolled in Cohort A and participants meeting Inclusion Criterion 2b will be enrolled in Cohort B.
  • (2a) Have locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease.

    • Relapsed with radiologic evidence of progression more than 1 year from completion of adjuvant endocrine therapy and have received no prior endocrine therapy for locoregionally recurrent or metastatic disease (Note: prior adjuvant endocrine therapy for localized disease may have included, but is not limited to, anti-estrogens or aromatase inhibitors. In addition, a participant may be enrolled if she has received ≤2 weeks of NSAI in this disease setting immediately preceding screening and agrees to discontinue NSAI until study treatment initiation.) OR
    • Presented de novo metastatic breast cancer (mBC) and not received any prior endocrine therapy.
  • (2b) Have locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease.

    • Relapsed with radiologic evidence of progression while receiving neoadjuvant or adjuvant endocrine therapy, with no subsequent endocrine therapy received following progression OR
    • Relapsed with radiologic evidence of progression within 1 year from completion of adjuvant endocrine therapy, with no subsequent endocrine therapy received following progression OR
    • Relapsed with radiologic evidence of progression more than 1 year from completion of adjuvant endocrine therapy and then subsequently relapsed with radiologic evidence of progression after receiving treatment with either an antiestrogen or an aromatase inhibitor as firstline endocrine therapy for metastatic disease. Participants may not have received more than 1 line of endocrine therapy or any prior chemotherapy for metastatic disease OR
    • Presented de novo with metastatic disease and then relapsed with radiologic evidence of progression after receiving treatment with either an antiestrogen or an aromatase inhibitor as first-line endocrine therapy for metastatic disease. Participants may not have received more than 1 line of endocrine therapy or any prior chemotherapy for metastatic disease.
  • Have postmenopausal status defined as meeting at least 1 of the following:

    • Prior bilateral oophorectomy
    • Age ≥60 years
    • Age <60 years and amenorrheic for at least 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH) and estradiol levels in the postmenopausal range.
  • Have 1 of the following, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1:

    • Measurable disease
    • Nonmeasurable bone-only disease. Nonmeasurable bone-only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft tissue component, or mixed lytic-blastic bone lesions without a measurable soft tissue component.
  • Have a performance status (PS) of ≤1 on the Eastern Cooperative Oncology (ECOG) scale.
  • Have adequate organ function, including:

    • Hematologic: absolute neutrophil count (ANC) ≥1.5 × 109/Liter (L), platelets

      ≥100 × 109/L, and hemoglobin ≥8 g/deciliter (dL). Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator; however, initial study drug treatment must not begin earlier than the day after the erythrocyte transfusion.

    • Hepatic: Total bilirubin ≤1.5 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

      ≤3.0 times ULN (or ALT and AST ≤5 times ULN if liver metastases are present).

    • Renal: serum creatinine ≤1.5 times ULN.
  • Have 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 (until the toxicity resolves to either baseline or at least Grade 1) except for residual alopecia or peripheral neuropathy.
  • Are able to swallow capsules.
  • Are reliable, willing to be available for the duration of the study, and willing to follow study procedures.

Exclusion Criteria:

  • Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. Visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of the disease.
  • Have inflammatory breast cancer.
  • Have clinical evidence or a history of central nervous system (CNS) metastasis. Screening test is not required for enrollment.
  • Are currently receiving or have previously received chemotherapy for locoregionally recurrent or metastatic breast cancer. (Note: Participants may be enrolled if they received prior [neo]adjuvant chemotherapy for localized disease.)
  • Have received prior treatment with everolimus or fulvestrant (for Cohort B only).
  • Have received prior treatment with any cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) inhibitor (or participated in any CDK4 and CDK6 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 enrolled in a clinical trial involving an investigational product (IP) or non-approved use of a drug or device (other than the IP/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. If a participant is currently enrolled in a clinical trial involving non-approved use of a device, then agreement with the investigator and Eli Lilly and Company (Lilly) clinical research physician (CRP) is required to establish eligibility.
  • 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 to allow for post-operative healing of the surgical wound and site(s).
  • Have received recent (within 28 days prior to randomization) live attenuated vaccines such as yellow fever vaccine.
  • Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study (eg, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis).
  • Have a personal history within the last 12 months of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest.
  • Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years.
  • Have received an autologous or allogeneic stem-cell transplant.
  • Have clinical evidence of active bacterial or fungal infection or active viral infection that, in the judgment of the investigator, would preclude participation in this study (eg, human immunodeficiency virus [HIV] or viral hepatitis). Screening test is not required for enrollment.

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): NCT02763566


Locations
Show Show 45 study locations
Sponsors and Collaborators
Eli Lilly and Company
Investigators
Layout table for investigator information
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
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol  [PDF] May 14, 2019
Statistical Analysis Plan  [PDF] April 25, 2019

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02763566    
Other Study ID Numbers: 15530
I3Y-CR-JPBQ ( Other Identifier: Eli Lilly and Company )
First Posted: May 5, 2016    Key Record Dates
Results First Posted: March 30, 2020
Last Update Posted: June 11, 2021
Last Verified: May 16, 2021
Keywords provided by Eli Lilly and Company:
Hormone Receptor-Positive
HER2-Negative
CDK4
CDK6
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Fulvestrant
Anastrozole
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
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists