Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

Recurrent Rectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01105377
• Other study ID #: NCI-2010-02024
• Secondary ID: NCI-2010-02024CD
• Status: Completed
• Phase: Phase 2
• First received: April 15, 2010
• Last updated: July 30, 2014
• Start date: April 2010
• Est. completion date: May 2014

Study information

• Verified date: July 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: May 2014
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• entinostat
Given orally
• azacitidine
Given SC

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	University of Southern California/Norris Cancer Center	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Metro-Minnesota CCOP	Saint Louis Park	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Lakeview Hospital	Stillwater	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No