A Neoadjuvant Study of Abemaciclib (LY2835219) in Postmenopausal Women With Hormone Receptor Positive, HER2 Negative Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the biological effects of abemaciclib in combination with anastrozole and compare those to the effects of abemaciclib alone and anastrozole alone in the tumors of postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer.

Official Title
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neoMONARCH: A Phase 2 Neoadjuvant Trial Comparing the Biological Effects of 2 Weeks of Abemaciclib (LY2835219) in Combination With Anastrozole to Those of Abemaciclib Monotherapy and Anastrozole Monotherapy and Evaluating the Clinical Activity and Safety of a Subsequent 14 Weeks of Therapy With Abemaciclib in Combination With Anastrozole in Postmenopausal Women With Hormone Receptor Positive, HER2 Negative Breast Cancer

Conditions
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Breast Cancer, Hormone Receptor Positive Tumor, Early-Stage Breast Carcinoma

Intervention / Treatment
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* Drug: Abemaciclib
* Drug: Loperamide
* Drug: Anastrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have postmenopausal status. Adenocarcinoma of the breast. Breast tumor ≥1 centimeter (cm) in diameter, HR+, HER2-. Neoadjuvant endocrine monotherapy is deemed to be a suitable therapy. Primary breast cancer that is suitable for baseline core biopsy. Have adequate organ function. Exclusion Criteria: Bilateral invasive breast cancer. Metastatic breast cancer (local spread to axillary lymph nodes is permitted). Inflammatory breast cancer. Prior systemic therapy or radiotherapy for invasive or non-invasive breast cancer in the same breast as currently being treated. Prior radiotherapy to the ipsilateral chest wall for any malignancy. Prior anti-estrogen therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abemaciclib + Anastrozole<br>Abemaciclib (150 milligrams [mg]) was given orally every 12 hours (Q12H) plus anastrozole (1 mg) orally once daily (QD) for 2 weeks. Loperamide was given as a prophylaxis for 4 weeks and then at physician discretion. All participants received abemaciclib (150 mg) orally Q12H plus anastrozole (1 mg) QD for an additional 14 weeks. Total treatment duration was 16 weeks. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Loperamide<br>* Administered orally<br>Drug: Anastrozole<br>* Administered orally<br>|
| Experimental: Abemaciclib<br>Abemaciclib (150 mg) was given orally Q12H for 2 weeks. Loperamide was given as a prophylaxis for 4 weeks and then at physician discretion. All participants received abemaciclib (150 mg) orally Q12H plus anastrozole (1 mg) QD for an additional 14 weeks. Total treatment duration was 16 weeks. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Loperamide<br>* Administered orally<br>Drug: Anastrozole<br>* Administered orally<br>|
| Active Comparator: Anastrozole<br>Anastrozole (1 mg) is given orally QD for 2 weeks. All participants received abemaciclib (150 mg) orally Q12H plus anastrozole (1 mg) QD for an additional 14 weeks. Loperamide was given as a prophylaxis for the first 2 weeks of the combination treatment and then at physician discretion. Total treatment duration was 16 weeks. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Loperamide<br>* Administered orally<br>Drug: Anastrozole<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to 2 Weeks in Ki67 Expression | Tumor tissue collected through a core biopsy at baseline and at the end of cycle 1 was used to determine Ki67 expression. Ki67 expression is defined as the percent of cells staining positive by validated central assay. | Baseline, 2 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathologic Complete Response (pCR) | pCR is defined as absence of invasive cancer in the breast and sampled regional lymph nodes. | From Start of Treatment Up to 16 Weeks | 
| Percentage of Participants With Complete Response (CR) or Partial Response (PR): Clinical Objective Response | Clinical objective response is defined as the percentage of participants with the best overall response rate (ORR) with a best OR of CR or PR, according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST) v1.1. ORR is recorded from the start of the study treatment until the earliest of objective progression or start of new anticancer therapy. A responder depends on target and non-target disease and the appearance of new lesions. CR is defined as the disappearance of all non-target lesions. PR is at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. All lymph nodes are non-pathological or normal in size (<10mm short axis). Progressive disease (PD) is a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, a relative increase of 20%, the sum must also demonstrate an absolute increase of 5 mm. | From Start of Treatment to Objective Progression or Start of New Anticancer Therapy (Up to 16 Weeks) | 
| Percentage of Participants With Complete Radiologic Response or Partial Radiological Response: Radiological Response | Radiological response is the percentage of participants with CR or, PR according to RECIST v.1.1. A responder is defined as any participant who exhibits a CR or PR. CR is the disappearance of all target lesions. PR is a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. PD is 20% increase in the sum of diameters of target lesions taking as reference the smallest sum and the appearance of 1 or more new lesions. | From Start of Treatment to Objective Progression or Start of New Anticancer Therapy (Up to 16 Weeks) | 
| Change From Baseline to Week 2 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | EORTC QLQ-C30 v3.0 was a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, emotional, cognitive, or social functioning), global health status and symptom scales of fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, or 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. | Baseline, 2 Weeks | 
| Pharmacokinetics (PK): Apparent Clearance of Abemaciclib | Abemaciclib apparent clearance (CL/F) was calculated by population nonlinear mixed effects modeling (NONMEM) using all available data spanning cycles 1 and cycles 3-5. | Cycle(C)1, Day(D)1: 2 to 4 Hours (Hrs) Postdose; C1D14: 4 Hrs Postdose, 7 Hrs Postdose; C3D1: Predose, 3 Hrs Postdose, C4D1 & C5D1, Predose, C5D28: Predose, 3 Hrs Postdose | 
| PK: Apparent Volume of Distribution of Abemaciclib | Abemaciclib apparent volume of distribution was calculated by population NONMEM using all available data spanning cycles 1 and cycles 3-5. | Cycle(C)1, Day(D)1: 2 to 4 Hours (Hrs) Postdose; C1D14: 4 Hrs Postdose, 7 Hrs Postdose; C3D1: Predose, 3 Hrs Postdose, C4D1 & C5D1, Predose, C5D28: Predose, 3 Hrs Postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cyclin-dependent kinase (CDK) 4/6 inhibitor, CDK 4 and 6 inhibitor