Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving azacitidine together with entinostat works in treating patients with metastatic colorectal 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
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PRIMARY OBJECTIVES: 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. SECONDARY OBJECTIVES: 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. TERTIARY OBJECTIVES: I. Evaluate changes in promoter methylation of selected genes from DNA in circulating serum samples. 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 toxicity. 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 conducted. After completion of study therapy, patients are followed up every 3-6 months for up to 3 years.

Official Title
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Phase II Study of Azacitadine and Entinostat in Patients With Metastatic Colorectal Cancer

Conditions
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Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Intervention / Treatment
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* Drug: entinostat
* Drug: azacitidine
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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 following: 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 C) More than 4 weeks since prior major surgical procedure No prior histone deacetylase inhibitors (including valproic acid) or demethylating agents No concurrent investigational agents No concurrent combination antiretroviral therapy in HIV-positive patients No concurrent investigational or commercial anticancer agents or therapies

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (entinostat, azacitidine)<br>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 toxicity. | Drug: entinostat<br>* Given orally<br>* Other names: SNDX-275;Drug: azacitidine<br>* Given SC<br>* Other names: Vidaza;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Tumor Response | Each evaluable patient is classified as having a confirmed tumor response if they have either a complete response (CR) or partial response (PR) lasts at least 4 weeks. Tumor response is measured by using RECIST v1.1 (Response Evaluation Criteria in Solid Tumors). A CR is defined as a disappearance of all target lesions, and each target lymph node must have reduction in short axis to <1.0 cm. A PR is defined as a 30% decrease in the sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation, compared to pre-treatment measurements. The confirmed response rate is calculated as the number of confirmed CR+PR, divided by the total number of evaluable patients, with 95% confidence intervals estimated using the approach of Duffy and Santner. | At 6 month evaluation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to disease progression (TTP) is defined as the time from the start of treatment to the earliest of the date documenting disease progression or most recent assessment for patients having no progression. The distribution of TTP is estimated using the method of Kaplan-Meier. | From the start of treatment to the earliest of the date documenting disease progression, assessed up to 3 years |