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Phase II Study of Azacitidine and Entinostat in Patients With Metastatic Colorectal Cancer

Phase 2
18 Years
Open (Enrolling)
Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

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Trial Information

Phase II Study of Azacitidine and Entinostat in Patients With Metastatic Colorectal Cancer


I. To determine the preliminary efficacy via Response Evaluation Criteria In Solid Tumors
(RECIST) response rate of the combination of azacitidine and entinostat in patients with
metastatic colorectal cancer.


I. Explore the effects of azacitidine and entinostat on time to progression in patients with
metastatic colorectal cancer.

II. To assess the toxicity for combination azacitidine and entinostat therapy.


I. Evaluate changes in promoter methylation of selected genes from DNA in circulating serum

II. To determine changes in histone deacetylase activity and acetylation of H3 and H4
histones in pre- and post-treatment tumor biopsies.

III. To evaluate correlations between these molecular effects and clinical outcomes
(response, time to progression).

IV. To correlate response rates by RECIST criteria versus response rates determined be EASL
(change in tumor enhancement).

OUTLINE: This is a multicenter study.

Patients receive azacitidine subcutaneously on days 1-5 and 8-10 and oral entinostat on days
3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable

Blood and tumor tissue samples are collected at baseline and periodically during courses 1-3
for DNA methylation, histone deacetylation activity, and acetylation of H3 and H4 histones
analysis by PCR, western blot, and RT-PCR assays. Pharmacogenomic studies may also be

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

Inclusion Criteria:

- Histologically confirmed metastatic colorectal cancer

- Measurable disease

- Patient has failed ≥ 2 prior chemotherapy regimens

- Not a candidate for curative resection

- No CNS metastases within ≤ 2 years

- Treatment for brain metastasis and whole brain disease that has remained stable
for > 3 months allowed

- Patients who have not been treated with steroid therapy may be allowed

- ECOG performance status 0-1

- Life expectancy ≥ 12 weeks

- Leukocytes ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Sensory neuropathy ≤ grade 2 allowed

- Willing to provide tissue and blood samples

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to entinostat, azacitidine, mannitol, or other agents used in
the study

- No uncontrolled intercurrent illness including, but not limited to, any of the

- Ongoing or active infection

- NYHA class II-IV symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

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

- No history of severe bleeding without thrombocytopenia

- No concurrent radiotherapy including palliative treatment

- Toxicities from prior therapy have resolved to ≤ grade 1

- More than 4 weeks since prior chemotherapy (> 6 weeks for nitrosoureas or mitomycin

- More than 4 weeks since prior major surgical procedure

- No prior histone deacetylase inhibitors (including valproic acid) or demethylating

- No concurrent investigational agents

- No concurrent combination antiretroviral therapy in HIV-positive patients

- No concurrent investigational or commercial anticancer agents or therapies

Type of Study:


Study Design:

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

Outcome Measure:

Proportion of confirmed tumor responses defined to be either a CR or PR as measured by RECIST criteria version 1.1

Outcome Description:

The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated using the approach of Duffy and Santner.

Outcome Time Frame:

At 6 months

Safety Issue:


Principal Investigator

Nilofer Azad

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

April 2010

Completion Date:

Related Keywords:

  • Recurrent Colon Cancer
  • Recurrent Rectal Cancer
  • Stage IV Colon Cancer
  • Stage IV Rectal Cancer
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Colorectal Neoplasms



Johns Hopkins University Baltimore, Maryland  21205
Mayo Clinic Rochester, Minnesota  55905
Washington University School of Medicine Saint Louis, Missouri  63110
University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15213
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Mayo Clinic in Arizona Scottsdale, Arizona  85259-5404
Mayo Clinic in Florida Jacksonville, Florida  32224
Wayne State University Detroit, Michigan  48202
Metro-Minnesota CCOP St. Louis Park, Minnesota  
University of Southern California Los Angeles, California  90033