Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer
Conditions
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.
Interventions
DRUGentinostat
Given orally
DRUGazacitidine
Given SC
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
This study opened 4/12/2010, registered 24 participants (Cohort I), and suspended accrual due to toxicity on 9/10/2010. The study registered 23 participants (Cohort II) after re-opening 5/4/2011 with more restrictive eligibility criteria and closed 12/8/2011. The primary endpoint is evaluated using participants registered onto Cohort II.
Pre-assignment details
Interim evaluation of the first 24 participants revealed more extensive disease than expected. Eligibility criteria were modified (as reflected in the Eligibility Criteria section) and registered another 23 patients (Cohort II). One patient in Cohort II cancelled prior to initiating study treatment and is not evaluable for the primary endpoint.
Participants by arm
| Arm | Count |
|---|---|
| Cohort I Treatment Prior to Eligibility Criteria Amendment: Participants 1-24 were registered according to the Eligibility Criteria for Cohort I detailed in this report. Participants received 40 mg/m\^2 azacitidine subcutaneously on days 1-5 and 8-10 and 7 mg oral entinostat on days 3 and 10. Courses repeat every 28 days until disease progression or unacceptable toxicity. | 24 |
| Cohort II Treatment After Eligibility Criteria Amendment: Participants 25-47 were registered according to the eligibility requirements detailed in the Eligibility Criteria section of this report for Cohort II, which contains more restrictive criteria than Cohort I. Study treatment remained the same as Cohort I. Participants receive 40 mg/m\^2 azacitidine subcutaneously on days 1-5 and 8-10 and 7 mg oral entinostat on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 23 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort I | Cohort II | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years | 62.6 years | 58.0 years |
| Region of Enrollment United States | 24 participants | 23 participants | 47 participants |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 24 | 22 / 22 |
| serious Total, serious adverse events | 12 / 24 | 5 / 22 |
Outcome results
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.
Time frame: At 6 month evaluation
Population: Analysis was performed per protocol using only Cohort II participants, except those deemed ineligible, cancelled, or in major treatment violation during cycle 1. One of the 23 Cohort II participants was excluded in the analysis due to cancelling before initiating treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort II | Confirmed Tumor Response | 0 percentage of participants |
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.
Time frame: From the start of treatment to the earliest of the date documenting disease progression, assessed up to 3 years
Population: Analysis for this endpoint was per protocol and two participants were excluded. One participant in Cohort I was ineligible and one participant in Cohort II refused to start their 1st cycle of study treatment (ie, cancelled). Therefore, 23 participants in Cohort I and 22 participants in Cohort II were analyzed for this secondary endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I | Time to Progression | 1.8 months |
| Cohort II | Time to Progression | 1.9 months |