search
Back to results

Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer

Primary Purpose

Male Breast Carcinoma, Recurrent Breast Carcinoma, Stage IIIC Breast Cancer AJCC v7

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Azacitidine
Entinostat
Laboratory Biomarker Analysis
Pharmacological Study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Male Breast Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient must have histologically or cytologically confirmed adenocarcinoma of the breast triple-negative (ER-, progesterone receptor [PR]-, human epidermal growth factor receptor 2 [HER2]-) or hormone positive/ HER2-, with evidence of locally advanced and inoperable or metastatic disease (American Joint Committee on Cancer [AJCC] Stage IV)

    • NOTE: Triple-negative patients will be defined per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines; these guidelines state that ER and PR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls
    • A patient who has a change in receptor status (e.g., PR negative to positive) may be stratified as triple negative or hormone positive, contrary to the most recent receptor testing, for the purposes of the study based upon the clinical course at the discretion of the Study Chair; for HER2 assessment, a negative result is an immuno-histochemistry staining of 0 or 1+, a fluorescence in situ hybridization (FISH) result of less than 4.0 HER2 gene copies per nucleus, or a FISH ratio of less than 1.8
  • Patients with triple negative disease must have progressed through at least 1 prior chemotherapy regimen (administered in the adjuvant or metastatic setting); hormone receptor-positive patients must have progressed through two lines of hormonal therapy (administered in the adjuvant or metastatic setting), unless otherwise eligible as per below, and at least 1 prior chemotherapy regimen (administered in the adjuvant or metastatic setting) with no known curative options available

    • NOTE: Patients with hormone receptor-positive disease may be considered eligible if deemed clinically hormone-resistant taking into consideration the rate of progression of disease or a short interval of time on first line hormonal therapy before progression, or if intolerant of hormonal therapy such that further hormonal therapy will not be considered as part of the treatment strategy
  • In patients with metastatic disease in the liver, liver disease burden is limited to no more than 30% of total liver volume as assessed by local review
  • Patients must have measurable disease
  • Life expectancy of >= 12 weeks
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Hemoglobin (HgB) >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelet count >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); an exception to this may be allowed for participants with Gilbert's syndrome with documented approval by the Protocol Chair
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x ULN
  • Creatinine =< institutional ULN or creatinine clearance >= 60 mL/min using the Modified Cockcroft-Gault formula
  • Negative (serum or urine) pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Patient must have an accessible tumor lesion from which a biopsy specimen can be obtained; NOTE: if baseline biopsy is attempted and is unsuccessful (eg, patient intolerance, inadequate tissue), the patient will still be considered eligible for the study
  • Ability to understand and the willingness to sign a written informed consent document
  • Willingness to provide tissue and blood samples for mandatory translational research
  • Willingness to return to the enrolling institution for follow-up

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
    • NOTE: should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Any of the following:

    • Chemotherapy < 3 weeks prior to registration
    • Hormone therapy < 3 weeks prior to registration
    • Radiotherapy < 3 weeks prior to registration
    • Surgery < 3 weeks prior to registration
    • Nitrosoureas/mitomycin C < 6 weeks prior to registration
    • Trastuzumab < 6 weeks prior to registration
    • Bevacizumab < 6 weeks prior to registration
    • Those who have not recovered from acute adverse events to grade < 2 or baseline due to agents administered, with exception of alopecia, unless approved by the Protocol Chair
    • NOTE: concurrent bisphosphonate therapy is allowed; concurrent ovarian suppression therapy (i.e., Lupron or Zoladex) is also allowed at the discretion of the Protocol Chair/designee
  • Any other ongoing investigational agents
  • Known sensitivity to 5-AZA, entinostat or mannitol
  • Uncontrolled intercurrent illness that in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including, but not limited to:

    • Ongoing or active infection
    • Symptomatic congestive heart failure (New York Heart Association [NYHA] class II or above)
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness/social situations that would limit compliance with study requirements
    • Other co-morbid systemic illness or other severe concurrent disease
  • Active malignancy other than breast cancer =< 3 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
  • Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive
  • Received prior treatment with HDAC (histone deacetylase) inhibitors or demethylating agents =< 2 weeks prior to registration
  • Unstable brain metastases; NOTE: patients with brain metastases must have stable neurologic status and magnetic resonance imaging (MRI) imaging following local therapy (surgery or radiation) for at least 4 weeks, with no dexamethasone requirement (stable low dose dexamethasone allowed at discretion of Study Chair); patients with leptomeningeal disease are not eligible
  • Patient taking valproic acid
  • Patient who cannot swallow tablets

Sites / Locations

  • City of Hope Comprehensive Cancer Center
  • USC / Norris Comprehensive Cancer Center
  • University of California Davis Comprehensive Cancer Center
  • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Unity Hospital
  • Metro Minnesota Community Oncology Research Consortium
  • University of Pittsburgh Cancer Institute (UPCI)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (entinostat and azacitidine)

Arm Description

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Outcomes

Primary Outcome Measures

Confirmed Response Rate (Percentage of Participants With Complete or Partial Response Noted as the Objective Status on Two Consecutive Evaluations at Least 4 Weeks Apart) Assessed by RECIST
Percentage of participants with complete or partial response will be estimated independently for each cohort by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

Clinical Benefit Rate
Clinical benefit rate estimated by the number of patients who achieve a confirmed response plus the number of patients who have stable disease for a duration of at least 6 months divided by the total number of evaluable patients. All evaluable patients will be used for this analysis.
Overall Survival
Median number of months alive, estimated by Kaplan-Meier method.
Progression-free Survival (PFS)
Median number of months without progression. Estimated using the method of Kaplan-Meier.

Full Information

First Posted
May 6, 2011
Last Updated
October 24, 2023
Sponsor
National Cancer Institute (NCI)
search

1. Study Identification

Unique Protocol Identification Number
NCT01349959
Brief Title
Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer
Official Title
Phase II Study of Azacitidine and Entinostat (SNDX-275) in Patients With Advanced Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 21, 2011 (Actual)
Primary Completion Date
March 27, 2014 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well giving azacitidine and entinostat work in treating patients with advanced breast cancer. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST) criteria of the combination of azacitidine (5-AZA) and entinostat in women with advanced breast cancer; triple-negative and hormone-refractory. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of the combination of 5-AZA and entinostat in women with advanced breast cancer. II. To determine progression-free survival, overall survival, and clinical benefit rate of the combination of 5-AZA and entinostat. TERTIARY OBJECTIVES: I. To collect safety and toxicity data as well as the feasibility and response rate where hormonal therapy is added to the combination under investigation at the time of progressive disease. (Exploratory) II. To determine the pharmacokinetic profile of 5-AZA (full profile) and entinostat (trough concentrations) in patients with advanced breast cancer. (Exploratory) III. To assess serum cytidine deaminase pharmacogenetics and phenotypic activity as a potential biomarker of response to 5-AZA. (Exploratory) IV. To evaluate baseline and change in candidate gene re-expression (e.g., estrogen receptor [ER] alpha, retinoic acid receptor [RAR] beta) in malignant tissue obtained from selected patients through fine-needle aspiration (FNA) and core biopsy, prior to and following combination therapy. (Exploratory) V. To evaluate baseline and change in gene methylation silencing in circulating deoxyribonucleic acid (DNA) obtained prior to and following combination therapy. (Exploratory) VI. To evaluate baseline and change in gene methylation in malignant tissue obtained through FNA and core biopsy. (Exploratory) OUTLINE: This is a multicenter study. Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10, and entinostat orally (PO) on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring. After completion of study therapy, patients are followed up every 3-6 months for up to 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Male Breast Carcinoma, Recurrent Breast Carcinoma, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7, Triple-Negative Breast Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (entinostat and azacitidine)
Arm Type
Experimental
Arm Description
Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, Vidaza
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
Entinostat
Other Intervention Name(s)
HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Confirmed Response Rate (Percentage of Participants With Complete or Partial Response Noted as the Objective Status on Two Consecutive Evaluations at Least 4 Weeks Apart) Assessed by RECIST
Description
Percentage of participants with complete or partial response will be estimated independently for each cohort by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Clinical Benefit Rate
Description
Clinical benefit rate estimated by the number of patients who achieve a confirmed response plus the number of patients who have stable disease for a duration of at least 6 months divided by the total number of evaluable patients. All evaluable patients will be used for this analysis.
Time Frame
Up to 3 years
Title
Overall Survival
Description
Median number of months alive, estimated by Kaplan-Meier method.
Time Frame
Up to 3 years
Title
Progression-free Survival (PFS)
Description
Median number of months without progression. Estimated using the method of Kaplan-Meier.
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Number of Participants With Change in Expression of Relevant Genes (e.g., ER Alpha and RAR Beta) Evaluated by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)
Description
Number of participants with a change in candidate gene re-expression of ER-alpha and RAR beta evaluated by reverse transcriptase polymerase chain reaction (RT-PCR).
Time Frame
Baseline to up to 8 weeks
Title
Circulating DNA Evaluated Using QM-MSP
Description
Data will also be graphically displayed showing trend in median values across time. Nonparametric Wilcoxon signed rank tests will be used to determine whether or not the data shows evidence of changes from baseline.
Time Frame
Up to 8 weeks
Title
Confirmed Response Rate to Azacitidine and Entinostat Plus the Addition of Hormone Therapy
Description
Will be estimated in each cohort. All evaluable patients who receive hormonal therapy will be used for this analysis.
Time Frame
Up to 3 years
Title
Feasibility of the Addition of Hormone Therapy, Evaluated by Calculating the Number of Patients With Disease Progression That go on to Receive Hormonal Therapy
Time Frame
Up to 3 years
Title
Number of Participants With Change in Gene Methylation Evaluated Using Quantitative Multiple Methylation-specific Polymerase Chain Reaction (QM-MSP)
Time Frame
Up to 8 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient must have histologically or cytologically confirmed adenocarcinoma of the breast triple-negative (ER-, progesterone receptor [PR]-, human epidermal growth factor receptor 2 [HER2]-) or hormone positive/ HER2-, with evidence of locally advanced and inoperable or metastatic disease (American Joint Committee on Cancer [AJCC] Stage IV) NOTE: Triple-negative patients will be defined per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines; these guidelines state that ER and PR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls A patient who has a change in receptor status (e.g., PR negative to positive) may be stratified as triple negative or hormone positive, contrary to the most recent receptor testing, for the purposes of the study based upon the clinical course at the discretion of the Study Chair; for HER2 assessment, a negative result is an immuno-histochemistry staining of 0 or 1+, a fluorescence in situ hybridization (FISH) result of less than 4.0 HER2 gene copies per nucleus, or a FISH ratio of less than 1.8 Patients with triple negative disease must have progressed through at least 1 prior chemotherapy regimen (administered in the adjuvant or metastatic setting); hormone receptor-positive patients must have progressed through two lines of hormonal therapy (administered in the adjuvant or metastatic setting), unless otherwise eligible as per below, and at least 1 prior chemotherapy regimen (administered in the adjuvant or metastatic setting) with no known curative options available NOTE: Patients with hormone receptor-positive disease may be considered eligible if deemed clinically hormone-resistant taking into consideration the rate of progression of disease or a short interval of time on first line hormonal therapy before progression, or if intolerant of hormonal therapy such that further hormonal therapy will not be considered as part of the treatment strategy In patients with metastatic disease in the liver, liver disease burden is limited to no more than 30% of total liver volume as assessed by local review Patients must have measurable disease Life expectancy of >= 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Hemoglobin (HgB) >= 9.0 g/dL Absolute neutrophil count (ANC) >= 1,500/mcL Platelet count >= 100,000/mcL Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); an exception to this may be allowed for participants with Gilbert's syndrome with documented approval by the Protocol Chair Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x ULN Creatinine =< institutional ULN or creatinine clearance >= 60 mL/min using the Modified Cockcroft-Gault formula Negative (serum or urine) pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Patient must have an accessible tumor lesion from which a biopsy specimen can be obtained; NOTE: if baseline biopsy is attempted and is unsuccessful (eg, patient intolerance, inadequate tissue), the patient will still be considered eligible for the study Ability to understand and the willingness to sign a written informed consent document Willingness to provide tissue and blood samples for mandatory translational research Willingness to return to the enrolling institution for follow-up Exclusion Criteria: Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception NOTE: should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Any of the following: Chemotherapy < 3 weeks prior to registration Hormone therapy < 3 weeks prior to registration Radiotherapy < 3 weeks prior to registration Surgery < 3 weeks prior to registration Nitrosoureas/mitomycin C < 6 weeks prior to registration Trastuzumab < 6 weeks prior to registration Bevacizumab < 6 weeks prior to registration Those who have not recovered from acute adverse events to grade < 2 or baseline due to agents administered, with exception of alopecia, unless approved by the Protocol Chair NOTE: concurrent bisphosphonate therapy is allowed; concurrent ovarian suppression therapy (i.e., Lupron or Zoladex) is also allowed at the discretion of the Protocol Chair/designee Any other ongoing investigational agents Known sensitivity to 5-AZA, entinostat or mannitol Uncontrolled intercurrent illness that in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including, but not limited to: Ongoing or active infection Symptomatic congestive heart failure (New York Heart Association [NYHA] class II or above) Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements Other co-morbid systemic illness or other severe concurrent disease Active malignancy other than breast cancer =< 3 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive Received prior treatment with HDAC (histone deacetylase) inhibitors or demethylating agents =< 2 weeks prior to registration Unstable brain metastases; NOTE: patients with brain metastases must have stable neurologic status and magnetic resonance imaging (MRI) imaging following local therapy (surgery or radiation) for at least 4 weeks, with no dexamethasone requirement (stable low dose dexamethasone allowed at discretion of Study Chair); patients with leptomeningeal disease are not eligible Patient taking valproic acid Patient who cannot swallow tablets
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vered Stearns
Organizational Affiliation
Johns Hopkins University/Sidney Kimmel Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Comprehensive Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
USC / Norris Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
University of California Davis Comprehensive Cancer Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Unity Hospital
City
Fridley
State/Province
Minnesota
ZIP/Postal Code
55432
Country
United States
Facility Name
Metro Minnesota Community Oncology Research Consortium
City
Saint Louis Park
State/Province
Minnesota
ZIP/Postal Code
55416
Country
United States
Facility Name
University of Pittsburgh Cancer Institute (UPCI)
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
24583822
Citation
Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, Topper MJ, Luo J, Connolly RM, Azad NS, Stearns V, Pardoll DM, Davidson N, Jones PA, Slamon DJ, Baylin SB, Zahnow CA, Ahuja N. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014 Feb 15;5(3):587-98. doi: 10.18632/oncotarget.1782.
Results Reference
derived

Learn more about this trial

Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer

We'll reach out to this number within 24 hrs