Breast Cancer
Conditions
Brief summary
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.
Interventions
DRUGenzastaurin
1125 milligram (mg) loading dose then 250 mg, oral, twice daily (for a total of 500 mg), until disease progression
DRUGplacebo
oral, daily
DRUGfulvestrant
500 mg, intramuscular (IM), day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate) | Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR]) | Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks) | 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. |
| Duration of Clinical Benefit | Time of Clinical Benefit to Progressive Disease or Death (Up to 3 Years) | 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. |
| Progression Free Survival (PFS) | Baseline to Measured Progressive Disease or Death Due to Any Cause (Up to 3 Years) | 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. |
| Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | From Baseline to Study Completion (Up to 3 years, 9 months) | 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. |
| Percentage of Participants With Enzastaurin Biomarkers and Disease State | Baseline, Cycle 2 to Study Completion (Up to 3 Years, 9 Months) | — |
Countries
France, Germany, Italy, Netherlands, Spain
Participant flow
Pre-assignment details
Completers include participants who had died from any cause, who discontinued due to progressive disease or were alive and on study but no longer receiving treatment at end of the study.
Participants by arm
| Arm | Count |
|---|---|
| Enzastaurin + Fulvestrant BID Participants received Enzastaurin 1125 mg loading dose then 250 mg, oral, twice daily (BID) (for a total of 500 mg), until disease progression
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. | 39 |
| Enzastaurin + Fulvestrant QD Participants received Enzastaurin 1125 mg loading dose then received Enzastaurin once daily (QD) regimen of enzastaurin 500 mg orally QD in a 28-day cycle until disease progression.
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 Ful 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter. | 55 |
| Placebo + Fulvestrant BID 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. | 58 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 0 |
Baseline characteristics
| Characteristic | Enzastaurin + Fulvestrant BID | Enzastaurin + Fulvestrant QD | Placebo + Fulvestrant BID | Total |
|---|---|---|---|---|
| Age, Continuous | 62.2 years STANDARD_DEVIATION 9.1 | 66.5 years STANDARD_DEVIATION 10.3 | 65.4 years STANDARD_DEVIATION 10 | 64.9 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 57 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 55 Participants | 1 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 38 Participants | 55 Participants | 58 Participants | 151 Participants |
| Region of Enrollment France | 11 Participants | 24 Participants | 25 Participants | 60 Participants |
| Region of Enrollment Germany | 3 Participants | 6 Participants | 10 Participants | 19 Participants |
| Region of Enrollment Italy | 7 Participants | 6 Participants | 5 Participants | 18 Participants |
| Region of Enrollment Netherlands | 9 Participants | 5 Participants | 6 Participants | 20 Participants |
| Region of Enrollment Spain | 9 Participants | 14 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Female | 39 Participants | 55 Participants | 58 Participants | 152 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 78 / 94 | 31 / 39 | 47 / 55 | 50 / 58 |
| serious Total, serious adverse events | 17 / 94 | 9 / 39 | 8 / 55 | 11 / 58 |
Outcome results
Primary
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.
Time frame: Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzastaurin + Fulvestrant QD + BID | Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate) | 43.6 percentage of participants |
| Enzastaurin + Fulvestrant BID | Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate) | 43.6 percentage of participants |
| Enzastaurin + Fulvestrant QD | Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate) | 43.6 percentage of participants |
| Fulvestrant + Placebo | Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate) | 44.8 percentage of participants |
p-value: 0.6238Fisher Exact
p-value: 0.6282Fisher Exact
p-value: 0.6242Fisher Exact
Secondary
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 frame: Time of Clinical Benefit to Progressive Disease or Death (Up to 3 Years)
Population: All randomized participants who received at least one dose of study drug and had evaluable clinical benefit duration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin + Fulvestrant QD + BID | Duration of Clinical Benefit | 9.6 months |
| Enzastaurin + Fulvestrant BID | Duration of Clinical Benefit | 9.4 months |
| Enzastaurin + Fulvestrant QD | Duration of Clinical Benefit | 9.6 months |
| Fulvestrant + Placebo | Duration of Clinical Benefit | 9.7 months |
p-value: 0.8582Log Rank
p-value: 0.7307Log Rank
p-value: 0.9798Log Rank
Secondary
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.
Time frame: From Baseline to Study Completion (Up to 3 years, 9 months)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enzastaurin + Fulvestrant QD + BID | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Adverse Events (AEs) | 3 Participants |
| Enzastaurin + Fulvestrant QD + BID | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 0 Participants |
| Enzastaurin + Fulvestrant BID | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 0 Participants |
| Enzastaurin + Fulvestrant BID | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Adverse Events (AEs) | 1 Participants |
| Enzastaurin + Fulvestrant QD | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 0 Participants |
| Enzastaurin + Fulvestrant QD | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Adverse Events (AEs) | 2 Participants |
| Fulvestrant + Placebo | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 1 Participants |
| Fulvestrant + Placebo | Number of Participants Who Discontinued With Adverse Events (AE) and Serious Adverse Events (SAEs) | Adverse Events (AEs) | 1 Participants |
Secondary
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.
Time frame: Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzastaurin + Fulvestrant QD + BID | Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR]) | 5.3 percentage of participants |
| Enzastaurin + Fulvestrant BID | Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR]) | 5.1 percentage of participants |
| Enzastaurin + Fulvestrant QD | Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR]) | 5.5 percentage of participants |
| Fulvestrant + Placebo | Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR]) | 5.2 percentage of participants |
p-value: 0.639Fisher Exact
p-value: 0.6721Fisher Exact
p-value: 0.6349Fisher Exact
Secondary
Percentage of Participants With Enzastaurin Biomarkers and Disease State
Time frame: Baseline, Cycle 2 to Study Completion (Up to 3 Years, 9 Months)
Population: Zero participants were analyzed due to insufficient samples being collected.
Secondary
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.
Time frame: Baseline to Measured Progressive Disease or Death Due to Any Cause (Up to 3 Years)
Population: All randomized participants who had received at least one dose of study drug and had evaluable PFS data. Participants were censored in Fulvestrant + Enzastaurin (QD) arm = 4, the Fulvestrant + Enzastaurin (BID) arm = 6, and the Fulvestrant + Placebo arm = 6.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin + Fulvestrant QD + BID | Progression Free Survival (PFS) | 5.2 months |
| Enzastaurin + Fulvestrant BID | Progression Free Survival (PFS) | 3.7 months |
| Enzastaurin + Fulvestrant QD | Progression Free Survival (PFS) | 6.0 months |
| Fulvestrant + Placebo | Progression Free Survival (PFS) | 5.5 months |
p-value: 0.5887Log Rank
p-value: 0.4516Log Rank
p-value: 0.7965Log Rank