Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

Phase 2

Completed

Conditions: Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer

Interventions: Drug: entinostat
Drug: azacitidine
Other: laboratory biomarker analysis

Registration Number: NCT01105377

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 47

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (entinostat, azacitidine)	entinostat	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.
Treatment (entinostat, azacitidine)	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.
Treatment (entinostat, azacitidine)	laboratory biomarker analysis	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.

Primary Outcome Measures

Name	Time	Method
Confirmed Tumor Response	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

Name	Time	Method
Time to Progression	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.

Trial Locations

Locations (14): University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
Mayo Clinic in Arizona
🇺🇸
Scottsdale, Arizona, United States
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
🇺🇸
Baltimore, Maryland, United States
Minnesota Oncology Hematology PA-Maplewood
🇺🇸
Maplewood, Minnesota, United States
United Hospital
🇺🇸
Saint Paul, Minnesota, United States
Metro-Minnesota CCOP
🇺🇸
Saint Louis Park, Minnesota, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
University of Pittsburgh Cancer Institute
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Lakeview Hospital
🇺🇸
Stillwater, Minnesota, United States
Mayo Clinic in Florida
🇺🇸
Jacksonville, Florida, United States
University of Southern California/Norris Cancer Center
🇺🇸
Los Angeles, California, United States