Enzastaurin Plus Fulvestrant vs. Placebo Plus Fulvestrant in Breast Cancer

Study Overview
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Brief Summary
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The primary purpose of this study is to help answer the following research question: whether enzastaurin given together with fulvestrant can help participants who have breast cancer and make the tumor smaller or disappear and for how long.

Official Title
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A Randomized, Double-Blind, Phase II Trial of Fulvestrant Plus Enzastaurin Versus Fulvestrant Plus Placebo in Aromatase Inhibitor-Resistant Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: enzastaurin
* Drug: placebo
* Drug: fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female participants with a histological-documented diagnosis of locally advanced or metastatic breast cancer. The primary or metastatic tumor must be estrogen response (ER) and/or parathyroid hormone receptor (PtR) positive. Note: Hormone receptor positivity is defined as ER or PtR greater than 10 fmol/mg by biochemical assay or 10% positive cells by immunohistochemistry Participants are resistant to aromatase inhibitors (AI) therapy Females with postmenopausal status Previous radiation therapy is allowed, but should have been limited Measurable or non-measurable disease Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale Have adequate organ function Have an estimated life expectancy of at least 24 weeks Must sign an informed consent document Exclusion Criteria: Have had prior treatment with fulvestrant or enzastaurin Are receiving concurrent administration of any other antitumor therapy, with the exception of gonadotropin-releasing hormone (GnRH) antagonists. Have received treatment within the last 4 weeks with a drug that has not received regulatory approval for any indication at the time of study entry Have received supplemental estrogen or progesterone within 4 weeks prior to study entry Are hormone estrogen receptor (HER2)-positive Are unable to discontinue use of anticoagulants Have hypercalcemia Have a second primary malignancy that is clinically detectable at the time of consideration for study enrollment Have documented central nervous system (CNS) metastases, symptomatic pulmonary lymphangitis, or involvement of more than 1/3 of the liver Have a serious concomitant systemic disorder Have a serious cardiac condition Are unwilling or unable to discontinue use of carbamazepine, phenobarbital, or phenytoin at least 14 days prior to study therapy Are unable to swallow tablets.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzastaurin + Fulvestrant<br>Participants received Enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 500 mg orally (QD) once daily in a 28-day cycle. Participants received enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 250 mg orally (BID) twice daily in a 28-day cycle. Fulvestrant was given intramuscularly at a loading dose of 500 mg on Day 1 and 250 mg on Day 15 in Cycle 1. Subsequent doses of Fulvestrant 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter. | Drug: enzastaurin<br>* 1125 milligram (mg) loading dose then 250 mg, oral, twice daily (for a total of 500 mg), until disease progression<br>* Other names: LY317615;Drug: fulvestrant<br>* 500 mg, intramuscular (IM), day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression<br>|
| Placebo Comparator: Fulvestrant + Placebo<br>Participants received fulvestrant: 500 mg, IM, day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression. Then, participants received placebo, oral, daily. | Drug: placebo<br>* oral, daily<br>Drug: fulvestrant<br>* 500 mg, intramuscular (IM), day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate) | Clinical benefit rate is defined as the rate of confirmed CR, confirmed PR, and SD for 24 weeks duration and is the best response CR, PR, or SD as classified by the investigators according to the RECIST v1.1. CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of not-target lesions or appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameter since treatment started. Kaplan-Meier (KM) techniques were used to assess the time-to-event endpoints. Progressive Disease (PD) was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir. | Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR]) | The ORR is equal to the percentage of participants achieving a best overall response of partial response or complete response (PR + CR), according to RECIST version 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes must have reduction in short axis to <10 millimeter (mm) and normalization of tumor marker level of non-target lesions; PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions; PD was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir; SD was defined as small changes that did not meet above criteria. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. The 95% confidence interval (CI) was calculated by exact method. Kaplan-Meier (KM) techniques were used to assess the time-to-event endpoints. | Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks) | 
| Duration of Clinical Benefit | The duration of clinical benefit was measured from the time of clinical benefit of CR, PR or SD to the time of progressive disease or death from any cause. PD was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir. Kaplan-Meier (KM) techniques were used to assess the time-to-event endpoints. | Time of Clinical Benefit to Progressive Disease or Death (Up to 3 Years) | 
| Progression Free Survival (PFS) | Progression-free survival (PFS) time was defined as the time from baseline to the first date of progressive disease (symptomatic or objective) or death due to any cause, whichever occurred first. PD was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir.For participants who were not known to have died or progressed as of the data-inclusion cutoff date, PFS time was censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systematic anticancer therapy. PFS was summarized using Kaplan-Meier estimates. | Baseline to Measured Progressive Disease or Death Due to Any Cause (Up to 3 Years) | 
| Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs, regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. Participants who discontinued due to an AE or SAE are reported. | From Baseline to Study Completion (Up to 3 years, 9 months) | 
| Percentage of Participants With Enzastaurin Biomarkers and Disease State |  | Baseline, Cycle 2 to Study Completion (Up to 3 Years, 9 Months) |