Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

NCT ID: NCT01105377

Last Updated: 2014-08-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30
• Study Completion Date: 2014-05-31

Brief Summary

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

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.

Conditions

Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (entinostat, azacitidine)

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.

Group Type: EXPERIMENTAL

entinostat

Intervention Type: DRUG

Given orally

azacitidine

Intervention Type: DRUG

Given SC

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

entinostat

Given orally

Intervention Type: DRUG

azacitidine

Given SC

Intervention Type: DRUG

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

HDAC inhibitor SNDX-275; SNDX-275; 5-AC; 5-azacytidine; azacytidine; Vidaza

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nilofer Azad

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Arizona

Scottsdale, Arizona, United States

University of Southern California/Norris Cancer Center

Los Angeles, California, United States

Mayo Clinic in Florida

Jacksonville, Florida, United States

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, United States

Minnesota Oncology Hematology PA-Maplewood

Maplewood, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

Metro-Minnesota CCOP

Saint Louis Park, Minnesota, United States

United Hospital

Saint Paul, Minnesota, United States

Lakeview Hospital

Stillwater, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 24583822 (View on PubMed)

Other Identifiers

NCI-2010-02024

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000670136

Identifier Type: -

Identifier Source: secondary_id

MC084B

Identifier Type: OTHER

Identifier Source: secondary_id

8341

Identifier Type: OTHER

Identifier Source: secondary_id

N01CM00099

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA015083

Identifier Type: NIH

Identifier Source: secondary_id

View Link

N01CM00038

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2010-02024

Identifier Type: -

Identifier Source: org_study_id