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Phase II Study of Azacitidine and Entinostat (SNDX-275) in Patients With Advanced Breast Cancer

Phase 2
18 Years
Open (Enrolling)
Estrogen Receptor-negative Breast Cancer, Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Male Breast Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer, Triple-negative Breast Cancer

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Trial Information

Phase II Study of Azacitidine and Entinostat (SNDX-275) in Patients With Advanced Breast Cancer


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.


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.


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., ERalpha, RARbeta) 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 are stratified according to hormone receptor
status (triple negative vs resistant).

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. Patients undergo blood and tumor tissue sample collection at
baseline and periodically during therapy for correlative studies.

After completion of study therapy, patients are followed up every 3-6 months for up to 3

Inclusion Criteria:

- Patient must have histologically or cytologically confirmed adenocarcinoma of the
breast triple-negative (estrogen receptor [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

- 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

- 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)

- 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 because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate

- NOTE: the effects of 5-AZA and entinostat on the developing human fetus at the
recommended therapeutic dose are unknown; for this reason, 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 (NYHA class II or above)

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Confirmed response rate (complete or partial response noted as the objective status on two consecutive evaluations at least 4 weeks apart) assessed by RECIST

Outcome Description:

The proportion of successes 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.

Outcome Time Frame:

Up to 3 years

Safety Issue:


Principal Investigator

Vered Stearns

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

April 2011

Completion Date:

Related Keywords:

  • Estrogen Receptor-negative Breast Cancer
  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Recurrent Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Triple-negative Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male



Johns Hopkins University Baltimore, Maryland  21205
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Montefiore Medical Center Bronx, New York  10467-2490
Mayo Clinic in Arizona Scottsdale, Arizona  85259-5404
Mayo Clinic in Florida Jacksonville, Florida  32224
City of Hope Duarte, California  91010
University of Pittsburgh Pittsburgh, Pennsylvania  15261
Metro-Minnesota CCOP St. Louis Park, Minnesota  
UC Davis Comprehensive Cancer Center Sacramento, California  95817
University of Southern California Los Angeles, California  90033
Penn State Milton S Hershey Medical Center Hershey, Pennsylvania  17033
Unity Hospital Fridley, Minnesota  55432
Magee-Womens Hospital of UPMC Pittsburgh, Pennsylvania  15213
University of Colorado Cancer Center - Anschutz Cancer Pavilion Aurora, Colorado  80045
Siteman Cancer Center at Washington University Saint Louis, Missouri  63110