Study of the Effect of the Addition of SNDX-275 (Entinostat) to Continued Aromatase Inhibitor (AI) Therapy in Postmenopausal Women With ER+ Breast Cancer Whose Disease is Progressing

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Multicenter Study of the Effect of the Addition of SNDX-275 to Continued Aromatase Inhibitor (AI) Therapy in Postmenopausal Women With ER+ Breast Cancer Whose Disease is Progressing

Conditions
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ER+ Breast Cancer

Intervention / Treatment
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* Drug: Entinostat
* Drug: Aromatase Inhibitor (AI) Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal female patients. Histologically or cytologically confirmed estrogen receptor-positive (ER+) breast cancer. 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. 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. Eastern Cooperative Oncology Group (ECOG) 0-1. Laboratory parameters: 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. Creatinine less than 2.5 times the upper limit of normal for the institution. aspartate aminotransferase (AST) and alanine aminotransferase (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: Discontinuation of AI therapy prior to study entry. Less than 3 months treatment with most recent AI. Rapidly progressive, life-threatening metastases, including any of the following: Symptomatic lymphangitic metastases. Patients with known active brain or leptomeningeal involvement. More than one prior chemotherapy for metastatic disease. Any chemotherapy within 3 months prior to study. Radiotherapy to measurable lesion within 2 months prior to study. Bisphosphonates initiated within 4 weeks prior to study start. Allergy to benzamides or inactive components of study drug. Previous treatment with entinostat or any other histone deacetylase (HDAC) inhibitor including valproic acid. Patient is currently receiving treatment with any agent listed on the prohibited medication list such as valproic acid or other systemic cancer agents Any concomitant medical condition that precludes adequate study treatment compliance or assessment, or increases patient risk in the opinion of the investigator: 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. Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, uncontrolled systemic infection, Other active malignancy within 5 years excluding basal cell carcinoma or cervical intraepithelial neoplasia [CIN / cervical carcinoma in situ] or melanoma in situ). Patient currently is enrolled in (or completed within 30 days before study drug administration) another investigational drug study.
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entinostat 5 mg + AI<br>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. | Drug: Entinostat<br>* Entinostat 5 mg PO every week<br>* Other names: SNDX-275;Drug: Aromatase Inhibitor (AI) Therapy<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 6, 28-day cycles | 
| 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. | Up to 6, 28-day cycles | 
| 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. | Up to 6, 28-day cycles + 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, estrogen receptor positive