Breast Cancer, Breast Cancer, Estrogen Receptor-Positive, ER+ Breast Cancer, Estrogen Receptor-Positive Breast Cancer
Conditions
Keywords
Breast Neoplasms, Breast Tumor, Mammary Neoplasms
Brief summary
The purpose of this study is to evaluate the safety and efficacy of entinostat in combination with exemestane in the treatment of advanced breast cancer.
Interventions
DRUGentinostat
Entinostat 5 mg tablet orally once per week
DRUGexemestane
Exemestane 25 mg tablet orally once daily
DRUGPlacebo
Placebo-matching entinostat tablet orally once per week
Sponsors
Syndax Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Postmenopausal female patients * Histologically or cytologically confirmed estrogen receptor positive (ER+) breast cancer * Relapsed or progressed on prior treatment with aromatase inhibitor (AI) * Metastatic disease must be measurable * Patients receiving palliative radiation at the non-target lesions must have a 2 week wash out period following completion of the treatment prior to enrollment * Patient may have had one prior chemotherapy as part of first line therapy as long as it was received before initiation of prior AI * Eastern Cooperative Oncology Group (ECOG) performance status: 0 to 1 * Laboratory parameters: a)Hemoglobin ≥ 9.0 g/dL; platelets ≥ 100.0 x 10\^9/L; Absolute Neutrophil Count (ANC ≥) 1.5 x 10\^9/L without the use of hematopoietic growth factors b)Creatinine less than 2.5 times the upper limit of normal for the institution c)Aspartate transaminase (AST) and alanine transaminase (ALT) less than 2.5 times the upper limit of normal for the institution * Able to understand and give written informed consent and comply with study procedures
Exclusion criteria
* Relapse on treatment with non-steroidal AI after less than 12 months for patients in the adjuvant setting * Progressive disease after less than 3 months treatment with most recent AI for patients with metastatic disease * Rapidly progressive, life-threatening metastases * Any palliative radiotherapy to the measurable lesion * Previous treatment with SNDX-275 or any other histone deacetylase (HDAC) inhibitor including valproic acid * Allergy to benzamides or inactive components of the study drug * A history of allergies to any active or inactive ingredients of exemestane * Any concomitant medical condition that precludes adequate study treatment compliance * Patient is currently enrolled in (or completed within 30 days before study drug administration) another investigational drug study * Patient is currently receiving treatment with valproic acid, Zolinza (vorinostat) or any other HDAC inhibitor or deoxyribonucleic acid (DNA) methyltransferase inhibitor or any systemic anticancer treatment (with the exception of Lupron)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From date of randomization to discontinuation due to disease progression or death up to primary completion date (Median follow-up 6 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From date of randomization to discontinuation due to disease progression or intolerable Adverse Event (AE) up to primary completion date (Median follow-up 6 months) | ORR is defined as the percentage of participants with response during treatment classified as complete response (CR) or partial response (PR), 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. |
| Clinical Benefit Rate (CBR) | From date of randomization to discontinuation due to disease progression or intolerable AE up to primary completion date (Median follow-up 6 months) | CBR is defined as the percentage of participants with overall response (CR + PR) plus stable disease (SD) for 6 months 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 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 PD, taking as reference the smallest sum LD since the treatment started. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | First dose to within 30 days of last dose of study drug (Up to Approximately 2 Years) | 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. A TEAE is an AE that starts after the administration of study drug. A SAE is any AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth effect or other significant medical hazard. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | First dose of study drug to end of study (Median follow-up 24 months in the EE arm and 26.4 months in the EP arm) | OS was defined as the number of months elapsed between the date of randomization and the date of death (whatever the cause). |
Countries
Canada, Czechia, Hungary, Russia, United States
Participant flow
Recruitment details
Participants took part in the study at 38 investigative sites in the United States, Canada, Czech Republic, Hungary and Russia from 13 June 2008 to 26 November 2012.
Pre-assignment details
Participants with a diagnosis of metastatic breast cancer were enrolled equally in one of two treatment arms: exemestane 25 mg plus entinostat 5 mg or exemestane 25 mg plus placebo.
Participants by arm
| Arm | Count |
|---|---|
| Exemestane 25 mg + Placebo Exemestane (Aromasin®) 25 mg tablets orally once daily plus a placebo-matching entinostat tablet orally once per week on Days 1, 8, 15 and 22 of each 28-day treatment cycle until development of progressive disease (PD) or unacceptable toxicity or closure of the study by the Sponsor, whichever occurred first. | 66 |
| Exemestane 25 mg + Entinostat 5 mg Exemestane (Aromasin®) 25 mg tablets orally once daily plus an entinostat 5 mg tablet orally once per week on Days 1, 8, 15 and 22 of each 28-day treatment cycle until development of progressive disease (PD) or unacceptable toxicity or closure of the study by the Sponsor, whichever occurred first. | 64 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 43 | 27 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Withdrew Consent | 1 | 8 |
Baseline characteristics
| Characteristic | Exemestane 25 mg + Placebo | Exemestane 25 mg + Entinostat 5 mg | Total |
|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 10.06 | 62.2 years STANDARD_DEVIATION 11.72 | 62.4 years STANDARD_DEVIATION 10.87 |
| Age, Customized 18 to 44 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Customized 45 to 64 years | 38 Participants | 32 Participants | 70 Participants |
| Age, Customized 65 to 74 years | 19 Participants | 19 Participants | 38 Participants |
| Age, Customized ≥75 years | 7 Participants | 10 Participants | 17 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score=0 | 50 Participants | 40 Participants | 90 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score=1 | 16 Participants | 24 Participants | 40 Participants |
| Height | 164.9 centimeters (cm) STANDARD_DEVIATION 6.38 | 162.7 centimeters (cm) STANDARD_DEVIATION 6.44 | 163.8 centimeters (cm) STANDARD_DEVIATION 6.48 |
| Race/Ethnicity, Customized Black/African American | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 65 Participants | 61 Participants | 126 Participants |
| Race/Ethnicity, Customized White | 61 Participants | 60 Participants | 121 Participants |
| Sex: Female, Male Female | 66 Participants | 64 Participants | 130 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 73.2 kilograms (kg) STANDARD_DEVIATION 17.47 | 75.6 kilograms (kg) STANDARD_DEVIATION 16.66 | 74.3 kilograms (kg) STANDARD_DEVIATION 17.05 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 66 | 58 / 63 |
| serious Total, serious adverse events | 8 / 66 | 10 / 63 |
Outcome results
Primary
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: From date of randomization to discontinuation due to disease progression or death up to primary completion date (Median follow-up 6 months)
Population: Full Analysis Set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exemestane 25 mg + Placebo | Progression-free Survival (PFS) | 2.27 months |
| Exemestane 25 mg + Entinostat 5 mg | Progression-free Survival (PFS) | 4.28 months |
p-value: 0.0695% CI: [0.49, 1.09]Log Rank
Secondary
Clinical Benefit Rate (CBR)
CBR is defined as the percentage of participants with overall response (CR + PR) plus stable disease (SD) for 6 months 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 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 PD, taking as reference the smallest sum LD since the treatment started.
Time frame: From date of randomization to discontinuation due to disease progression or intolerable AE up to primary completion date (Median follow-up 6 months)
Population: Full Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exemestane 25 mg + Placebo | Clinical Benefit Rate (CBR) | 25.8 percentage of participants |
| Exemestane 25 mg + Entinostat 5 mg | Clinical Benefit Rate (CBR) | 26.6 percentage of participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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. A TEAE is an AE that starts after the administration of study drug. A SAE is any AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth effect or other significant medical hazard.
Time frame: First dose to within 30 days of last dose of study drug (Up to Approximately 2 Years)
Population: Safety Population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exemestane 25 mg + Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 56 Participants |
| Exemestane 25 mg + Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 8 Participants |
| Exemestane 25 mg + Entinostat 5 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 60 Participants |
| Exemestane 25 mg + Entinostat 5 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAE | 10 Participants |
Secondary
Objective Response Rate (ORR)
ORR is defined as the percentage of participants with response during treatment classified as complete response (CR) or partial response (PR), 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.
Time frame: From date of randomization to discontinuation due to disease progression or intolerable Adverse Event (AE) up to primary completion date (Median follow-up 6 months)
Population: Full Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exemestane 25 mg + Placebo | Objective Response Rate (ORR) | 4.6 percentage of participants |
| Exemestane 25 mg + Entinostat 5 mg | Objective Response Rate (ORR) | 4.7 percentage of participants |
Other Pre-specified
Overall Survival (OS)
OS was defined as the number of months elapsed between the date of randomization and the date of death (whatever the cause).
Time frame: First dose of study drug to end of study (Median follow-up 24 months in the EE arm and 26.4 months in the EP arm)
Population: Full Analysis Set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exemestane 25 mg + Placebo | Overall Survival (OS) | 19.84 months |
| Exemestane 25 mg + Entinostat 5 mg | Overall Survival (OS) | 28.13 months |
p-value: 0.01895% CI: [0.36, 0.97]Log Rank