Clinical trial NCT01105377: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-04-16
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Confirmed Tumor Response
timeFrame: At 6 month evaluation
Secondary outcomes:
measure: Time to Progression
timeFrame: From the start of treatment to the earliest of the date documenting disease progression, assessed up to 3 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California/Norris Cancer Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology PA-Maplewood
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro-Minnesota CCOP
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Stillwater
country: United States
facility: Lakeview Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Mayo Clinic
name: Nilofer Azad
role: PRINCIPAL_INVESTIGATOR
References:
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.