A Study of Abemaciclib (LY2835219) Plus Tamoxifen or Abemaciclib Alone in Women With Metastatic Breast Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and efficacy of abemaciclib plus tamoxifen or abemaciclib alone in women with previously treated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic breast cancer.

Official Title
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A Randomized, Open-Label, Phase 2 Study of Abemaciclib Plus Tamoxifen or Abemaciclib Alone, in Women With Previously Treated Hormone Receptor-Positive, HER2-Negative, Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Abemaciclib
* Drug: Tamoxifen
* Drug: Prophylactic Loperamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of HR+, HER2- breast cancer. Relapsed or progressed following endocrine therapy. Have received prior treatment with at least 2 chemotherapy regimens, of which at least 1 but no more than 2 have been administered in the metastatic setting. Have the presence of measureable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale. Have discontinued previous therapies for cancer (including specifically, aromatase inhibitors, anti-estrogens, chemotherapy, radiotherapy, and immunotherapy) 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 (until the toxicity resolves to either baseline or at least Grade 1) except for residual alopecia or peripheral neuropathy. Have adequate organ function. Have negative serum pregnancy test within 7 days prior to the first dose of study treatment and agree to use highly effective precautions to prevent pregnancy during the study and for 3 weeks following last dose of study treatment. Are able to swallow oral medication. Exclusion Criteria: Have clinical evidence or history of central nervous system metastasis. Have a personal history of any of the following conditions: syncope of either unexplained or cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest. Have active bacterial or fungal infection (that is, requiring intravenous antibiotics at the time of initiating study treatment) and/or detectable viral infection. Have received treatment with a prior cyclin-dependent kinase (CDK4) and CDK 6 inhibitor. Have a preexisting chronic condition resulting in persistent diarrhea. Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of the cervix or breast), unless in complete remission with no therapy for a minimum of 3 years.

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 + Tamoxifen<br>Abemaciclib given orally every 12 hours (Q12H) in combination with tamoxifen given orally every day. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Tamoxifen<br>* Administered orally<br>|
| Experimental: Abemaciclib<br>Abemaciclib given orally Q12H. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;|
| Experimental: Abemaciclib + Prophylactic Loperamide<br>Abemaciclib given orally Q12H in combination with prophylactic loperamide given orally. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Prophylactic Loperamide<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression-free survival time was measured from the date of randomization to the date of investigator-determined objective progression as defined by RECIST v1.1, or death from any cause, whichever occurred first. Progressive disease (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. Participants 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. | Baseline to Objective Disease Progression or Death from Any Cause (Up to 21 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR): Percentage of Participants With a Complete Response (CR) or Partial Response (PR) | Objective response rate was defined as the percentage of participants with CR or PR according to RECIST v1.1. CR was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the LD (longest diameter) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. | Baseline to Objective Disease Progression (Up to 21 Months) | 
| Duration of Response (DoR) | DoR is defined as the time from the date of first evidence of a CR or PR to the date of objective progression or death from any cause, whichever is earlier as defined by Recist v1.1. CR was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR was 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. | Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up to 21 Months) | 
| Overall Survival (OS) |  | Baseline to Death from Any Cause (Approximately 36 Months) | 
| Pharmacokinetics (PK): Mean Single Dose Concentration of Abemaciclib and Its Metabolites | Mean single dose concentrations of Abemaciclib and its metabolites (M2 & M20) are reported. | Cycle (C) 1 Day (D) 1 post dose | 
| Pharmacokinetics (PK): Steady State Concentration of Abemaciclib and Its Metabolites | Mean steady state concentrations of Abemaciclib and its metabolites (M2 & M20) are reported. C=Cycle D= Day | Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1 post dose | 
| PK: Mean Single Dose Concentration of Tamoxifen and Endoxifen | Mean single dose concentrations of Tamoxifen and its metabolite (Endoxifen) were reported. | Cycle 1 Day 1 post dose | 
| PK: Multiple Dose Concentration of Tamoxifen and Endoxifen | Mean multiple dose concentrations of Tamoxifen and its metabolite (Endoxifen) were reported. | Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1 post dose | 
| Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | The EORTC QLQ-C30 self-reported general cancer instrument consists of 30 items covered by 1 of 3 dimensions: Global health status/quality of life (2 items) with scores ranging from 1 (Very Poor) to 7 (Excellent). 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) 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. | Baseline, 21 Months | 
| Change From Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf) | 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. | Baseline, 21 Months |