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Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT01105377
Recruitment Status : Completed
First Posted : April 16, 2010
Results First Posted : November 1, 2013
Last Update Posted : August 1, 2014
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
Interventions Drug: entinostat
Drug: azacitidine
Other: laboratory biomarker analysis
Enrollment 47
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.
Arm/Group Title Cohort I Cohort II
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 24 23
Completed 24 22
Not Completed 0 1
Reason Not Completed
Withdrawal by Subject             0             1
Arm/Group Title Cohort I Cohort II Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 24 23 47
Hide Baseline Analysis Population Description
All participants accrued to this study are included in the description of baseline patient demographics.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 24 participants 23 participants 47 participants
57.0
(28.0 to 75.0)
62.6
(32.1 to 75.1)
58.0
(28.0 to 75.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 23 participants 47 participants
Female
11
  45.8%
9
  39.1%
20
  42.6%
Male
13
  54.2%
14
  60.9%
27
  57.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 24 participants 23 participants 47 participants
24 23 47
1.Primary Outcome
Title Confirmed Tumor Response
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Cohort I Cohort II
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 22
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
0 [1] 
(NA to NA)
[1]
A 95% Confidence Interval was not estimated due to a lack of response.
2.Secondary Outcome
Title Time to Progression
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Cohort I Cohort II
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 23 22
Median (95% Confidence Interval)
Unit of Measure: months
1.8
(1.7 to 3.7)
1.9
(1.8 to 2.2)
Time Frame [Not Specified]
Adverse Event Reporting Description All participants receiving protocol treatment were evaluated for toxicity. 23 participants form Cohort I and 22 participants from Cohort II initiated treatment. Patients received 40 mg/m^2 azacitidine subcutaneously days 1-5 and 8-10 and 7 mg oral entinostat on days 3 and 10 in each 28 day cycle until disease progression or unacceptable toxicity.
 
Arm/Group Title Cohort I Cohort II
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Cohort I Cohort II
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Cohort I Cohort II
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   12/24 (50.00%)      5/22 (22.73%)    
Blood and lymphatic system disorders     
Anemia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Cardiac disorders     
Cardiac disorders - Other, specify  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Chest pain - cardiac  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Gastrointestinal disorders     
Abdominal pain  1  3/24 (12.50%)  3 0/22 (0.00%)  0
Colonic perforation  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Constipation  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Ileus  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Nausea  1  2/24 (8.33%)  2 1/22 (4.55%)  1
Small intestinal obstruction  1  0/24 (0.00%)  0 1/22 (4.55%)  1
General disorders     
Fatigue  1  3/24 (12.50%)  3 1/22 (4.55%)  1
Fever  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Infections and infestations     
Abdominal infection  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Lung infection  1  2/24 (8.33%)  2 0/22 (0.00%)  0
Sepsis  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Skin infection  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Wound infection  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Investigations     
Alanine aminotransferase increased  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Alkaline phosphatase increased  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Aspartate aminotransferase increased  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Blood bilirubin increased  1  0/24 (0.00%)  0 2/22 (9.09%)  2
Lipase increased  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Lymphocyte count decreased  1  6/24 (25.00%)  18 0/22 (0.00%)  0
Neutrophil count decreased  1  1/24 (4.17%)  1 1/22 (4.55%)  1
Platelet count decreased  1  0/24 (0.00%)  0 1/22 (4.55%)  1
White blood cell decreased  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Metabolism and nutrition disorders     
Acidosis  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Anorexia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Dehydration  1  2/24 (8.33%)  3 0/22 (0.00%)  0
Hyperglycemia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Hypoalbuminemia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Hypophosphatemia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Pain in extremity  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Proteinuria  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Renal and urinary disorders - Other, specify  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Urinary tract obstruction  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Respiratory, thoracic and mediastinal disorders     
Dyspnea  1  4/24 (16.67%)  4 1/22 (4.55%)  1
Hypoxia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Skin and subcutaneous tissue disorders     
Erythroderma  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cohort I Cohort II
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   24/24 (100.00%)      22/22 (100.00%)    
Blood and lymphatic system disorders     
Anemia  1  19/24 (79.17%)  46 18/22 (81.82%)  35
Blood and lymphatic system disorders - Other, specify  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Cardiac disorders     
Atrial fibrillation  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Eye disorders     
Retinal detachment  1  0/24 (0.00%)  0 1/22 (4.55%)  2
Gastrointestinal disorders     
Abdominal distension  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Abdominal pain  1  7/24 (29.17%)  8 3/22 (13.64%)  4
Ascites  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Bloating  1  2/24 (8.33%)  2 0/22 (0.00%)  0
Constipation  1  5/24 (20.83%)  9 4/22 (18.18%)  7
Diarrhea  1  6/24 (25.00%)  7 2/22 (9.09%)  3
Dry mouth  1  2/24 (8.33%)  2 0/22 (0.00%)  0
Gastric hemorrhage  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Gastrointestinal disorders - Other, specify  1  2/24 (8.33%)  2 0/22 (0.00%)  0
Gastrointestinal pain  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Mucositis oral  1  2/24 (8.33%)  3 0/22 (0.00%)  0
Nausea  1  17/24 (70.83%)  28 9/22 (40.91%)  11
Oral dysesthesia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Rectal hemorrhage  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Vomiting  1  14/24 (58.33%)  19 5/22 (22.73%)  6
General disorders     
Chills  1  2/24 (8.33%)  3 0/22 (0.00%)  0
Edema limbs  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Fatigue  1  19/24 (79.17%)  57 16/22 (72.73%)  30
Fever  1  2/24 (8.33%)  3 0/22 (0.00%)  0
Injection site reaction  1  4/24 (16.67%)  10 3/22 (13.64%)  5
Pain  1  0/24 (0.00%)  0 2/22 (9.09%)  2
Hepatobiliary disorders     
Hepatic hemorrhage  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Infections and infestations     
Eye infection  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Lung infection  1  1/24 (4.17%)  1 1/22 (4.55%)  1
Sinusitis  1  1/24 (4.17%)  1 2/22 (9.09%)  2
Soft tissue infection  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Upper respiratory infection  1  2/24 (8.33%)  3 0/22 (0.00%)  0
Urinary tract infection  1  1/24 (4.17%)  1 2/22 (9.09%)  2
Investigations     
Activated partial thromboplastin time prolonged  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Alanine aminotransferase increased  1  1/24 (4.17%)  1 1/22 (4.55%)  2
Alkaline phosphatase increased  1  7/24 (29.17%)  8 4/22 (18.18%)  6
Aspartate aminotransferase increased  1  0/24 (0.00%)  0 1/22 (4.55%)  2
Blood bilirubin increased  1  1/24 (4.17%)  1 0/22 (0.00%)  0
CD4 lymphocytes decreased  1  1/24 (4.17%)  2 0/22 (0.00%)  0
Creatinine increased  1  2/24 (8.33%)  4 0/22 (0.00%)  0
INR increased  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Lipase increased  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Lymphocyte count decreased  1  6/24 (25.00%)  11 3/22 (13.64%)  3
Neutrophil count decreased  1  1/24 (4.17%)  5 6/22 (27.27%)  8
Platelet count decreased  1  6/24 (25.00%)  8 7/22 (31.82%)  8
White blood cell decreased  1  2/24 (8.33%)  15 10/22 (45.45%)  16
Metabolism and nutrition disorders     
Anorexia  1  8/24 (33.33%)  11 7/22 (31.82%)  7
Dehydration  1  2/24 (8.33%)  4 0/22 (0.00%)  0
Hyperglycemia  1  4/24 (16.67%)  6 3/22 (13.64%)  5
Hypoalbuminemia  1  6/24 (25.00%)  11 2/22 (9.09%)  3
Hypocalcemia  1  2/24 (8.33%)  3 3/22 (13.64%)  3
Hypokalemia  1  3/24 (12.50%)  6 0/22 (0.00%)  0
Hyponatremia  1  4/24 (16.67%)  9 0/22 (0.00%)  0
Hypophosphatemia  1  1/24 (4.17%)  1 3/22 (13.64%)  6
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/24 (4.17%)  1 1/22 (4.55%)  1
Back pain  1  1/24 (4.17%)  1 1/22 (4.55%)  2
Bone pain  1  1/24 (4.17%)  1 1/22 (4.55%)  1
Muscle weakness lower limb  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Musculoskeletal and connective tissue disorder - Other, specify  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Myalgia  1  2/24 (8.33%)  2 0/22 (0.00%)  0
Pain in extremity  1  2/24 (8.33%)  2 1/22 (4.55%)  1
Nervous system disorders     
Dysgeusia  1  2/24 (8.33%)  2 1/22 (4.55%)  1
Headache  1  1/24 (4.17%)  1 2/22 (9.09%)  3
Paresthesia  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Peripheral sensory neuropathy  1  1/24 (4.17%)  3 0/22 (0.00%)  0
Psychiatric disorders     
Anxiety  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Depression  1  2/24 (8.33%)  2 0/22 (0.00%)  0
Insomnia  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Renal and urinary disorders     
Hematuria  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Proteinuria  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Reproductive system and breast disorders     
Uterine pain  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Respiratory, thoracic and mediastinal disorders     
Allergic rhinitis  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Cough  1  2/24 (8.33%)  3 1/22 (4.55%)  1
Dyspnea  1  2/24 (8.33%)  2 1/22 (4.55%)  1
Postnasal drip  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Respiratory, thoracic and mediastinal disorders - Other, specify  1  2/24 (8.33%)  2 0/22 (0.00%)  0
Skin and subcutaneous tissue disorders     
Alopecia  1  3/24 (12.50%)  3 0/22 (0.00%)  0
Dry skin  1  1/24 (4.17%)  2 0/22 (0.00%)  0
Erythema multiforme  1  3/24 (12.50%)  4 2/22 (9.09%)  3
Rash maculo-papular  1  1/24 (4.17%)  1 1/22 (4.55%)  1
Skin and subcutaneous tissue disorders - Other, specify  1  4/24 (16.67%)  4 1/22 (4.55%)  1
Urticaria  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Vascular disorders     
Flushing  1  1/24 (4.17%)  1 0/22 (0.00%)  0
Hypertension  1  1/24 (4.17%)  12 0/22 (0.00%)  0
Hypotension  1  2/24 (8.33%)  2 1/22 (4.55%)  1
Vascular disorders - Other, specify  1  0/24 (0.00%)  0 1/22 (4.55%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Nilofer S. Azad, M.D.
Organization: Johns Hopkins Oncology Center
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01105377     History of Changes
Other Study ID Numbers: NCI-2010-02024
NCI-2010-02024 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000670136
MC084B ( Other Identifier: Mayo Clinic )
8341 ( Other Identifier: CTEP )
N01CM00099 ( U.S. NIH Grant/Contract )
P30CA015083 ( U.S. NIH Grant/Contract )
N01CM00038 ( U.S. NIH Grant/Contract )
First Submitted: April 15, 2010
First Posted: April 16, 2010
Results First Submitted: August 29, 2013
Results First Posted: November 1, 2013
Last Update Posted: August 1, 2014