Azacitidine and Entinostat in Treating Patients With Stage I Non-Small Cell Lung Cancer That Has Been Removed By Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01207726
• Collaborator: (none)
• Enrollment: 13
• Locations: 9
• Arms: 2
• Duration (Months): 32
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study combines the deoxyribonucleic acid (DNA) methyltransferase inhibitor, 5-azacitidine (5-AZA), with an orally bioavailable histone deacetylase inhibitor, entinostat (SNDX-275), for the adjuvant treatment of patients with resected stage I non-small cell lung cancer (NCSLC).

Condition or Disease	Intervention/Treatment	Phase
Stage IA Non-Small Cell Lung Carcinoma; Stage IB Non-Small Cell Lung Carcinoma	Drug: Azacitidine; Drug: Entinostat; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the effect of 5-azacitidine and entinostat on the hazard of 3 year progression-free survival in patients with resected stage I non-small cell lung cancer.

SECONDARY OBJECTIVES:

1. To assess the safety, tolerability and toxicity of entinostat and 5-azacitidine in patients with resected stage I non-small cell lung cancer.

2. To explore the effect of entinostat and 5-azacitidine on median disease-free and overall survival in patients with resected stage I non-small cell lung cancer.

3. To assess the pharmacodynamic effects of 5-azacitidine and entinostat on DNA methylation and gene re-expression in patients with resected stage I NSCLC through analysis of sputum.

4. To estimate the effect of entinostat and 5-azacitidine on progression free survival comparing patients with N2 lymph nodes categorized as methylated pre-treatment with those who are categorized as unmethylated.

5. To establish factors that predict clinical outcome in patients treated with combination epigenetic therapy by performing genome-wide analyses on pre-treatment tumor DNA.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10 and entinostat orally (PO) once daily (QD) on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Adjuvant Combined Epigenetic Therapy With 5-Azacitidine and Entinostat in Resected Stage I Non-small Cell Lung Cancer Versus Standard Care
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (azacitidine, entinostat) Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Drug: Azacitidine; Given SC; Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar U-18496 Vidaza ; Drug: Entinostat; Given PO; Other Names: HDAC inhibitor SNDX-275 MS 27-275 MS-275 SNDX-275 ; Other: Laboratory Biomarker Analysis; Correlative studies
No Intervention: Arm II (standard of care) Patients receive standard of care.

Outcome Measures

Primary Outcome Measures

1. Disease-free Survival (DFS) [3 years]

   The DFS hazard rate and 95% confidence interval will be reported. At this time, event time distributions for disease-free survival in the two arms will be estimated with the method of Kaplan and Meier and compared using a stratified Cox-proportional hazards model (stratified for stage IA vs IB) with a two-sided alpha of 10%.

Secondary Outcome Measures

1. Factors That Predict Clinical Outcome in Patients Treated With Combination Epigenetic Therapy in Terms of Epigenomic Data Generated From the Illumina Platform [Up to 2 years]

   The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. For this reason, 13 pts were enrolled and data was not analyzed, for which we are unable to make any conclusions or report results.

2. Median Disease-free Survival [Up to 5 years]

   Determined by the method determined by Kaplan and Meier. Estimated with 95% confidence intervals. Cox proportional hazard modeling will be used for multivariate analysis.

3. Number of Relapses and Deaths Per Total Time of Follow-up Comparing Patients With N2 Lymph Nodes in Terms of Methylated and Unmethylated [Up to 5 years]

   Kaplan Meier curves will be used.

4. Overall Survival [Up to 5 years]

   Determined by the method determined by Kaplan and Meier. Estimated with 95% confidence intervals. Cox proportional hazard modeling will be used for multivariate analysis.

5. Presence of Methylation Patterns [Up to 2 years]

   McNemar's test will be used to compare the change in methylation after treatment in sputum.

6. Toxicities Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [Up to 5 years]

   Simple descriptive statistics will be utilized to display the data.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must be status post complete (R0) surgical resection of pathologically-proven NSCLC (stage IA-IB according to AJCC version 7)

• Patients must be at least 4 weeks out from completion of surgery

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 X institutional upper limit of normal

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal

• Creatinine =< 1.5 X institutional upper limit of normal

• The effects of entinostat and 5-azacitidine on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients must be within 8 weeks of completing surgery

• Patients who have received prior chemotherapy or radiation for treatment of their current diagnosis of lung cancer

• Patients with sub-lobar resections (ie: wedge resection or segmentectomy)

• Patients without mediastinal lymph node specimens from mediastinoscopy or surgery (at least level R4 or 7 for right sided tumors OR at least level 5, 6 or 7 for left sided tumors)

• Patients may not be receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat, 5-azacitidine or other agents used in the study

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study because entinostat and 5-azacitidine are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with entinostat or 5-azacitidine, breastfeeding should be discontinued if the mother is treated on this protocol; these potential risks may also apply to other agents used in this study

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with entinostat or 5-azacitidine; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Anne Arundel Medical Center	Annapolis	Maryland	United States	21401
4	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
5	Johns Hopkins Bayview Medical Center	Baltimore	Maryland	United States	21224
6	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
7	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15232
8	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
9	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Charles Rudin, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01207726
• Other Study ID Numbers: NCI-2012-02901; NCI-2012-02901; NA_00038631; J1037; 8311; P30CA006973
• First Posted: Sep 23, 2010
• Last Update Posted: Feb 5, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Azacitidine; Entinostat; Histone Deacetylase Inhibitors

Study Results

Participant Flow

Arm/Group Title	Azacitidine SC and Entinostat Oral	Chemotherapy Alone
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Standard of care chemotherapy
Period Title: Overall Study
STARTED	7	6
COMPLETED	7	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Azacitidine SC and Entinostat PO	Cytotoxic Therapy	Total
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Followed by Cytotoxic Therapy investigator Choice	Standard of care	Total of all reporting groups
Overall Participants	7	6	13
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 57.1%	1 16.7%	5 38.5%
>=65 years	3 42.9%	5 83.3%	8 61.5%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	66	68	67
Sex: Female, Male (Count of Participants)
Female	1 14.3%	2 33.3%	3 23.1%
Male	6 85.7%	4 66.7%	10 76.9%
Region of Enrollment (participants) [Number]
United States	7 100%	6 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	Disease-free Survival (DFS)
Description	The DFS hazard rate and 95% confidence interval will be reported. At this time, event time distributions for disease-free survival in the two arms will be estimated with the method of Kaplan and Meier and compared using a stratified Cox-proportional hazards model (stratified for stage IA vs IB) with a two-sided alpha of 10%.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. Data was not collected to assess this outcome measure.

Arm/Group Title	Arm I (Azacitidine, Entinostat)	Arm II (Standard of Care)
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Azacitidine: Given SC Entinostat: Given PO Laboratory Biomarker Analysis: Correlative studies	Patients receive standard of care.
Measure Participants	0	0

2. Secondary Outcome

Title	Factors That Predict Clinical Outcome in Patients Treated With Combination Epigenetic Therapy in Terms of Epigenomic Data Generated From the Illumina Platform
Description	The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. For this reason, 13 pts were enrolled and data was not analyzed, for which we are unable to make any conclusions or report results.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. Data was not collected to assess this outcome measure.

Arm/Group Title	Azacitidine SC and Entinostat Oral	Chemotherapy Alone
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Standard of care chemotherapy
Measure Participants	0	0

3. Secondary Outcome

Title	Median Disease-free Survival
Description	Determined by the method determined by Kaplan and Meier. Estimated with 95% confidence intervals. Cox proportional hazard modeling will be used for multivariate analysis.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. Data was not collected to assess this outcome measure.

Arm/Group Title	Azacitidine SC and Entinostat Oral	Chemotherapy Alone
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Standard of care chemotherapy
Measure Participants	0	0

4. Secondary Outcome

Title	Number of Relapses and Deaths Per Total Time of Follow-up Comparing Patients With N2 Lymph Nodes in Terms of Methylated and Unmethylated
Description	Kaplan Meier curves will be used.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. Data was not collected to assess this outcome measure.

Arm/Group Title	Azacitidine SC and Entinostat Oral	Chemotherapy Alone
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Standard of care chemotherapy
Measure Participants	0	0

5. Secondary Outcome

Title	Overall Survival
Description	Determined by the method determined by Kaplan and Meier. Estimated with 95% confidence intervals. Cox proportional hazard modeling will be used for multivariate analysis.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. Data was not collected to assess this outcome measure.

Arm/Group Title	Azacitidine SC and Entinostat PO	Cytotoxic Therapy
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Followed by Cytotoxic Therapy investigator Choice	Standard of care
Measure Participants	0	0

6. Secondary Outcome

Title	Presence of Methylation Patterns
Description	McNemar's test will be used to compare the change in methylation after treatment in sputum.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. Data was not collected to assess this outcome measure.

Arm/Group Title	Azacitidine SC and Entinostat Oral	Chemotherapy Alone
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Standard of care chemotherapy
Measure Participants	0	0

7. Secondary Outcome

Title	Toxicities Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0
Description	Simple descriptive statistics will be utilized to display the data.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

The study was terminated early due to poor accrual since the requirement of clinic administration of the 5AZA daily and post-operative patients not wanting 6 months of treatment. Data was not collected to assess this outcome measure.

Arm/Group Title	Azacitidine SC and Entinostat Oral	Chemotherapy Alone
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Standard of care chemotherapy
Measure Participants	0	0

Adverse Events

Time Frame	Up to 3 years
Arm/Group Title	Azacitidine SC and Entinostat PO		Cytotoxic Chemotherapy
Arm/Group Description	Patients receive azacitidine SC on days 1-5 and 8-10 and entinostat PO QD on days 3 and 10. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.		Investigators Choice Chemotherapy
All Cause Mortality
	Azacitidine SC and Entinostat PO		Cytotoxic Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)
Serious Adverse Events
	Azacitidine SC and Entinostat PO		Cytotoxic Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Azacitidine SC and Entinostat PO		Cytotoxic Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.