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

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

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.

Study Overview

• Status: Completed
• Conditions: ER+ Breast Cancer
• Intervention / Treatment: Drug: Entinostat; Drug: Aromatase Inhibitor (AI) Therapy

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland
    • St. Vincent's University Hospital
• United Kingdom
  • Birmingham, United Kingdom
    • The University of Birmingham
  • Cardiff, United Kingdom
    • Velindre Hospital - Whitchurch
  • Liverpool, United Kingdom
    • Whiston Hospital; Clatterbridge Centre for Oncology
  • London, United Kingdom
    • University College London Hospitals
  • Manchester, United Kingdom
    • Christie Hospital, Manchester Breast Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Entinostat; Entinostat 5 mg PO every week; Other Names: SNDX-275; Drug: Aromatase 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Syndax Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2008
• Primary Completion (ACTUAL): November 24, 2009
• Study Completion (ACTUAL): November 24, 2009

Study Registration Dates

• First Submitted: January 23, 2009
• First Submitted That Met QC Criteria: January 23, 2009
• First Posted (ESTIMATE): January 26, 2009

Study Record Updates

• Last Update Posted (ACTUAL): June 30, 2022
• Last Update Submitted That Met QC Criteria: June 6, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: breast cancer; estrogen receptor positive
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Steroid Synthesis Inhibitors; Estrogen Antagonists; Histone Deacetylase Inhibitors; Entinostat; Aromatase Inhibitors
• Other Study ID Numbers: SNDX-275-0303