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Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

Primary Purpose

Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
entinostat
azacitidine
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Colon Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Mayo Clinic in Arizona
  • University of Southern California/Norris Cancer Center
  • Mayo Clinic in Florida
  • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
  • Wayne State University/Karmanos Cancer Institute
  • Minnesota Oncology Hematology PA-Maplewood
  • Mayo Clinic
  • Metro-Minnesota CCOP
  • United Hospital
  • Lakeview Hospital
  • Washington University School of Medicine
  • University of Pittsburgh Cancer Institute
  • University of Pittsburgh
  • University of Wisconsin Hospital and Clinics

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (entinostat, azacitidine)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
April 15, 2010
Last Updated
July 30, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01105377
Brief Title
Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer
Official Title
Phase II Study of Azacitadine and Entinostat in Patients With Metastatic Colorectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
July 2014
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (entinostat, azacitidine)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
entinostat
Other Intervention Name(s)
HDAC inhibitor SNDX-275, SNDX-275
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
azacitidine
Other Intervention Name(s)
5-AC, 5-azacytidine, azacytidine, Vidaza
Intervention Description
Given SC
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Confirmed Tumor Response
Description
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.
Time Frame
At 6 month evaluation
Secondary Outcome Measure Information:
Title
Time to Progression
Description
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.
Time Frame
From the start of treatment to the earliest of the date documenting disease progression, assessed up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nilofer Azad
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
University of Southern California/Norris Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224-9980
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Wayne State University/Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Minnesota Oncology Hematology PA-Maplewood
City
Maplewood
State/Province
Minnesota
ZIP/Postal Code
55109
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Metro-Minnesota CCOP
City
Saint Louis Park
State/Province
Minnesota
ZIP/Postal Code
55416
Country
United States
Facility Name
United Hospital
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55102
Country
United States
Facility Name
Lakeview Hospital
City
Stillwater
State/Province
Minnesota
ZIP/Postal Code
55082
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
University of Pittsburgh Cancer Institute
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Facility Name
University of Wisconsin Hospital and Clinics
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
24583822
Citation
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.
Results Reference
derived

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Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

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