Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Stage IV Colon Cancer; Stage IV Rectal Cancer; Recurrent Colon Cancer; Recurrent Rectal Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: entinostat; Drug: azacitidine

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 Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California/Norris Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Minnesota
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology Hematology PA-Maplewood
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Saint Louis Park, Minnesota, United States, 55416
      • Metro-Minnesota CCOP
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Stillwater, Minnesota, United States, 55082
      • Lakeview Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Nilofer Azad, Mayo Clinic

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: April 15, 2010
• First Submitted That Met QC Criteria: April 15, 2010
• First Posted (Estimate): April 16, 2010

Study Record Updates

• Last Update Posted (Estimate): August 1, 2014
• Last Update Submitted That Met QC Criteria: July 30, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Recurrence; Rectal Neoplasms; Colonic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine; Histone Deacetylase Inhibitors; Entinostat
• Other Study ID Numbers: NCI-2010-02024 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA015083 (U.S. NIH Grant/Contract); N01CM00099 (U.S. NIH Grant/Contract); N01CM00038 (U.S. NIH Grant/Contract); 8341 (Other Identifier: CTEP); CDR0000670136; MC084B (Other Identifier: Mayo Clinic)