Clinical trial NCT02763566: A Study of Abemaciclib (LY2835219) in Participants With Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Hormone Receptor-Positive
HER2-Negative
CDK4
CDK6
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2016-05-05
Enrollment: 463
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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 with de novo metastatic breast cancer (mBC) and not received any prior endocrine therapy. OR
* Relapsed with radiologic evidence of progression less than 1 year from completion of or while receiving adjuvant endocrine therapy (except for letrozole or anastrozole) and have received no prior endocrine therapy for locoregionally recurrent or metastatic disease.
* (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 with de novo 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.

Primary outcomes:
measure: Progression Free Survival (PFS) (Abemaciclib + NSAI & Placebo NSAI)
timeFrame: Randomization to Measured Progressive Disease or Death (up to 26 Months)
Secondary outcomes:
measure: Progression Free Survival (PFS) (Abemaciclib + Fulvestrant and Placebo + Fulvestrant Arms)
timeFrame: Randomization to Measured Progressive Disease or Death (up to 26 Months)
measure: Overall Survival (OS)
timeFrame: Randomization to Date of Death from Any Cause (Estimated up to 38 Months)
measure: Percentage of Participants With Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
timeFrame: Randomization to Measured Progressive Disease (up to 26 Months)
measure: Duration of Response (DoR)
timeFrame: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 38 Months)
measure: Percentage of Participants Who Exhibit Stable Disease (SD) or CR or PR [Disease Control Rate (DCR)]
timeFrame: Randomization to Measured Progressive Disease (up to 26 Months)
measure: 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)]
timeFrame: Randomization to Measured Progressive Disease (up to 26 Months)
measure: Change From Randomization in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
timeFrame: Baseline through 19 Months
measure: Pharmacokinetics (PK): Area Under the Concentration Curve of Abemaciclib, Its Metabolites (M2 & M20)
timeFrame: C1D1 post dose, C2D1 post dose, C3D1 predose, C4D1 predose
Other outcomes:
Locations:
city: Ijui
country: Brazil
facility: ONCOSITE - Centro de Pesquisa Clinica em Oncologia
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Centro Gaucho Integrado De Oncologia, Hematologia, Ensino E Pesquisa
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: Fundação Pio XII - Hospital de Câncer de Barretos
state: Sao Paulo
city: São José do Rio Preto
country: Brazil
facility: Hospital de Base de Sao Jose do Rio Preto
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: Icesp - Instituto Do Câncer Do Estado de São Paulo
city: São Paulo
country: Brazil
facility: Clínica de Pesquisa e Centro de Estudos em Ginecologia Oncológica e Mamária LTDA
city: Bengbu
country: China
facility: Afflilated Hospital of Bengbu Medical College
state: Anhui
city: Beijing
country: China
facility: The Fifth Medical Center of PLA General Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Fuzhou
country: China
facility: Fujian Provincial Cancer hospital
state: Fujian
city: Fuzhou
country: China
facility: Fuzhou General hospital of Nanjing Military Command
state: Fujian
city: Nanning
country: China
facility: Guangxi Medical University Affiliated Tumor Hospital
state: Guang XI
city: Guangzhou
country: China
facility: Guangdong Province People's Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
state: Guangdong
city: Shijiazhuang
country: China
facility: The Fourth Hospital of Hebei Medical University
state: Hebei
city: Harbin
country: China
facility: Harbin Medical University Caner Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Wuhan Union Hospital Cancer Center
state: Hubei
city: Wuhan
country: China
facility: Tongji Hospital Tongji Medical, Science & Technology
state: Hubei
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Chang Chun
country: China
facility: Jilin Province Tumor Hospital
state: Ji Lin
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School
state: Jiangsu
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital
state: Jiangsu
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Dalian
country: China
facility: The 2nd Affiliated Hospital of Dalian Medical University
state: Liaoning
city: Shenyang
country: China
facility: Liaoning Cancer Hospital&Institute
state: Liaoning
city: Shenyang
country: China
facility: The first affiliated hospital of China medical university
state: Liaoning
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
state: Shaanxi
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Shanghai
country: China
facility: Shanghai General Hospital
state: Shanghai
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
state: Tianjin
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: The Second Affiliate Hospital of Zhejiang University School of medicine
state: Zhejiang
city: New Delhi
country: India
facility: Dr. B. L. Kapur Memorial Hospital
state: Delhi
city: Ahmedabad
country: India
facility: The Gujarat Cancer & Research Institute (GCRI)
state: Gujarat
city: Bangalore
country: India
facility: Healthcare Global Enterprises Limited (HCG)
state: Karnataka
city: Bangalore
country: India
facility: M S Ramaiah Medical College Hospitals
state: Karnataka
city: Mumbai
country: India
facility: Tata Memorial Hospital
state: Maharashtra
city: Pune
country: India
facility: Jehangir Hospital
state: Maharashtra
city: Ranipet
country: India
facility: Christian Medical College Vellore
state: Tamil Nadu
city: Kolkata
country: India
facility: Medica Superspecialty Hospital
state: West Bengal
city: Johannesburg
country: South Africa
facility: The Medical Oncology Centre of Rosebank
state: Gauteng
city: Pretoria
country: South Africa
facility: Eastleigh Breast Care Center
state: Gauteng
city: Johannesburg
country: South Africa
facility: Sandton Oncology Centre
Study officials:
affiliation: Eli Lilly and Company
name: 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)
role: STUDY_DIRECTOR
References:
citation: Zhang QY, Sun T, Yin YM, Li HP, Yan M, Tong ZS, Oppermann CP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ, Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD, Jiang ZF, Hu XC. MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2- advanced breast cancer: the multinational randomized phase III study. Ther Adv Med Oncol. 2020 Oct 22;12:1758835920963925. doi: 10.1177/1758835920963925. eCollection 2020.