Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

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.

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