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

Phase 2

Completed

• Conditions: ER+ Breast Cancer
• Interventions: Drug: Entinostat; Drug: Aromatase Inhibitor (AI) Therapy

• Registration Number: NCT00828854
• Lead Sponsor: Syndax Pharmaceuticals

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2008-10-01
• Study First Submitted: 2009-01-23
• Study First Submitted QC: 2009-01-23
• Study First Posted: 2009-01-26
• Primary Completion: 2009-11-24
• Study Completion: 2009-11-24
• Results First Submitted: 2021-05-04
• Status Verified: 2022-06
• Results First Submitted QC: 2022-06-06
• Last Update Submitted: 2022-06-06
• Results First Posted: 2022-06-30
• Last Update Posted: 2022-06-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 27

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Entinostat 5 mg + AI	Aromatase Inhibitor (AI) Therapy	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.
Entinostat 5 mg + AI	Entinostat	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.

Trial Locations

Locations (6)

University College London Hospitals; 🇬🇧 London, United Kingdom

Christie Hospital, Manchester Breast Centre; 🇬🇧 Manchester, United Kingdom

Velindre Hospital - Whitchurch; 🇬🇧 Cardiff, United Kingdom

Whiston Hospital; Clatterbridge Centre for Oncology; 🇬🇧 Liverpool, United Kingdom

St. Vincent's University Hospital; 🇮🇪 Dublin, Ireland

The University of Birmingham; 🇬🇧 Birmingham, United Kingdom