ER+ Breast Cancer
Conditions
Keywords
breast cancer, estrogen receptor positive
Brief summary
The addition of entinostat to an AI will result in a maximal abrogation of estrogen receptor-α mediated activity and inhibit mechanisms of resistance to the aromatase inhibitor. It is hypothesized that entinostat with continued AI will increase the estimated AI clinical benefit rate (CBR) from 5% to 25% with an acceptable safety profile.
Interventions
DRUGEntinostat
Entinostat 5 mg PO every week
DRUGAromatase Inhibitor (AI) Therapy
AI therapy at labeled dose and schedule as prescribed in clinical practice. AI therapies include: Arimidex® (anastrozole) 1 mg/day by mouth (PO), Fermara® (letrozole) 2.5 mg/day PO , Aromasin® (exemestane) 25 mg/day PO.
Sponsors
Syndax Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
1. Postmenopausal female patients. 2. Histologically or cytologically confirmed estrogen receptor-positive (ER+) breast cancer. 3. Progressive disease (PD) after at least 3 months on treatment with a 3rd generation AI in the advanced disease setting as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. 4. At least 1 measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral computed tomography (CT) scan with the last imaging performed within 4 weeks prior to study entry. If there is only one measurable lesion and it is located in previously irradiated field, it must have demonstrated progression according to RECIST criteria. 5. Eastern Cooperative Oncology Group (ECOG) 0-1. 6. Laboratory parameters: 1. Hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x10\^9/L; absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L without the use of hematopoietic growth factors. 2. Creatinine less than 2.5 times the upper limit of normal for the institution. 3. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 times the upper limit of normal for the institution. 7. Able to understand and give written informed consent and comply with study procedures.
Exclusion criteria
1. Discontinuation of AI therapy prior to study entry. 2. Less than 3 months treatment with most recent AI. 3. Rapidly progressive, life-threatening metastases, including any of the following: 1. Symptomatic lymphangitic metastases. 2. Patients with known active brain or leptomeningeal involvement. 4. More than one prior chemotherapy for metastatic disease. 5. Any chemotherapy within 3 months prior to study. 6. Radiotherapy to measurable lesion within 2 months prior to study. 7. Bisphosphonates initiated within 4 weeks prior to study start. 8. Allergy to benzamides or inactive components of study drug. 9. Previous treatment with entinostat or any other histone deacetylase (HDAC) inhibitor including valproic acid. 10. Patient is currently receiving treatment with any agent listed on the prohibited medication list such as valproic acid or other systemic cancer agents 11. Any concomitant medical condition that precludes adequate study treatment compliance or assessment, or increases patient risk in the opinion of the investigator: 1. Myocardial infarction or arterial thromboembolic events within 6 months, or experiencing severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease and a QTc interval \>0.47 second. 2. Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, uncontrolled systemic infection, 3. Other active malignancy within 5 years excluding basal cell carcinoma or cervical intraepithelial neoplasia \[CIN / cervical carcinoma in situ\] or melanoma in situ). 12. Patient currently is enrolled in (or completed within 30 days before study drug administration) another investigational drug study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | 6 months | CBR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR) or stable disease (SD) for 6 months as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to 6, 28-day cycles | PFS is defined as the number of months from the date of randomization to the earlier of progressive disease (PD) or death due to any cause. |
| Objective Response Rate (ORR) During the First 6 Cycles of Study Treatment | Up to 6, 28-day cycles | ORR is defined as the percentage of participants with response during treatment classified as CR or PR, as assessed by the investigator based on RECIST, version 1.0. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. |
| Number of Participants With Adverse Events (AEs) | Up to 6, 28-day cycles + 30 days | An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Worsening of a pre-existing medical condition was considered an AE if there was either an increase in severity, frequency, or duration of the condition or an association with significantly worse outcomes. Abnormal clinical laboratory findings determined by the investigator to be clinically significant were recorded as AEs. |
Countries
Ireland, United Kingdom
Participant flow
Recruitment details
Participants took part in the study at 8 investigative sites in the United Kingdom and Ireland from 1 October 2008 to 24 November 2009.
Pre-assignment details
Participants with a diagnosis of estrogen receptor-positive (ER+) breast cancer whose disease is progressing were enrolled to receive entinostat 5 mg in combination with continued aromatase Inhibitor (AI) therapy.
Participants by arm
| Arm | Count |
|---|---|
| Entinostat 5 mg + AI Entinostat 5 mg tablet orally every week on Days 1, 8. 15 and 22 of each 28-day treatment cycle in combination with continued treatment with AI therapy at labeled dose and schedule until disease progression or unacceptable toxicity. | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Disease Progression | 17 |
| Overall Study | Reason not Specified | 1 |
Baseline characteristics
| Characteristic | Entinostat 5 mg + AI |
|---|---|
| Age, Continuous | 68 years STANDARD_DEVIATION 7 |
| Age, Customized 45 to 64 years | 7 Participants |
| Age, Customized 65 to 74 years | 15 Participants |
| Age, Customized 75 years and older | 5 Participants |
| Eastern Cooperative Oncology Group (ECOG) Status Score=0 | 9 Participants |
| Eastern Cooperative Oncology Group (ECOG) Status Score=1 | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Region of Enrollment Ireland | 9 participants |
| Region of Enrollment United Kingdom | 18 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 15 / 27 |
Outcome results
Primary
Clinical Benefit Rate (CBR)
CBR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR) or stable disease (SD) for 6 months as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started.
Time frame: 6 months
Population: Per-protocol Set included participants from the full analysis who met eligibility criteria, completed at least 2 cycles and who had baseline and post-baseline tumor assessments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entinostat 5 mg + AI | Clinical Benefit Rate (CBR) | 15.4 percentage of participants |
Secondary
Number of Participants With Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Worsening of a pre-existing medical condition was considered an AE if there was either an increase in severity, frequency, or duration of the condition or an association with significantly worse outcomes. Abnormal clinical laboratory findings determined by the investigator to be clinically significant were recorded as AEs.
Time frame: Up to 6, 28-day cycles + 30 days
Population: Safety Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Entinostat 5 mg + AI | Number of Participants With Adverse Events (AEs) | 27 Participants |
Secondary
Objective Response Rate (ORR) During the First 6 Cycles of Study Treatment
ORR is defined as the percentage of participants with response during treatment classified as CR or PR, as assessed by the investigator based on RECIST, version 1.0. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD.
Time frame: Up to 6, 28-day cycles
Population: Per-protocol Set included participants from the full analysis who met eligibility criteria, completed at least 2 cycles and who had baseline and post-baseline tumor assessments
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entinostat 5 mg + AI | Objective Response Rate (ORR) During the First 6 Cycles of Study Treatment | 3.9 percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS is defined as the number of months from the date of randomization to the earlier of progressive disease (PD) or death due to any cause.
Time frame: Up to 6, 28-day cycles
Population: Per-protocol Set included participants from the full analysis who met eligibility criteria, completed at least 2 cycles and who had baseline and post-baseline tumor assessments
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Entinostat 5 mg + AI | Progression-Free Survival (PFS) | 3.9 months |