Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT01105377
• Recruitment Status: Completed
• First Posted: April 16, 2010
• Results First Posted: November 1, 2013
• Last Update Posted: August 1, 2014
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer	Drug: entinostat; Drug: azacitidine; Other: laboratory biomarker analysis	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Azacitadine and Entinostat in Patients With Metastatic Colorectal Cancer
• Study Start Date: April 2010
• Actual Primary Completion Date: March 2012
• Actual Study Completion Date: May 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: entinostat; Given orally; Other Names: HDAC inhibitor SNDX-275; SNDX-275; Drug: azacitidine; Given SC; Other Names: 5-AC; 5-azacytidine; azacytidine; Vidaza; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Confirmed Tumor Response [ Time Frame: At 6 month evaluation ]
   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.

Secondary Outcome Measures :

1. Time to Progression [ Time Frame: From the start of treatment to the earliest of the date documenting disease progression, assessed up to 3 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic in Arizona

Scottsdale, Arizona, United States, 85259

United States, California

University of Southern California/Norris Cancer Center

Los Angeles, California, United States, 90033

United States, Florida

Mayo Clinic in Florida

Jacksonville, Florida, United States, 32224-9980

United States, Maryland

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States, 21287

United States, Michigan

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Minnesota

Minnesota Oncology Hematology PA-Maplewood

Maplewood, Minnesota, United States, 55109

Mayo Clinic

Rochester, Minnesota, United States, 55905

Metro-Minnesota CCOP

Saint Louis Park, Minnesota, United States, 55416

United Hospital

Saint Paul, Minnesota, United States, 55102

Lakeview Hospital

Stillwater, Minnesota, United States, 55082

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Pennsylvania

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States, 15232

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15232

United States, Wisconsin

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Nilofer Azad; Mayo Clinic

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01105377
• Other Study ID Numbers: NCI-2010-02024; NCI-2010-02024 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000670136; MC084B ( Other Identifier: Mayo Clinic ); 8341 ( Other Identifier: CTEP ); N01CM00099 ( U.S. NIH Grant/Contract ); P30CA015083 ( U.S. NIH Grant/Contract ); N01CM00038 ( U.S. NIH Grant/Contract )
• First Posted: April 16, 2010
• Results First Posted: November 1, 2013
• Last Update Posted: August 1, 2014
• Last Verified: July 2014

Additional relevant MeSH terms:

Rectal Neoplasms; Colonic Neoplasms; Recurrence; Disease Attributes; Pathologic Processes; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Azacitidine; Entinostat; Histone Deacetylase Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors