Azacitidine and Entinostat in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer

Stage IV Non-Small Cell Lung Cancer Clinical Trial

Official title:

A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00387465
• Other study ID #: NCI-2009-00220
• Secondary ID: NCI-2009-00220CD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 2006
• Est. completion date: November 2014

Study information

• Verified date: April 2019
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I/II trial is studying the side effects and best dose of azacitidine when given together with entinostat and to see how well they work in treating patients with recurrent advanced non-small cell lung cancer. Azacitidine and 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.

Description:

PRIMARY OBJECTIVES:

I. To assess safety, characterize toxicities, and determine the maximum tolerated dose of 5-AZA (azacitidine) with a fixed-dose of entinostat in patients with recurrent advanced non-small cell lung cancer (NSCLC). (Phase I) II. To determine the objective response rate of 5-AZA and entinostat in patients with recurrent NSCLC. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetic profile of 5-AZA and entinostat in patients with recurrent NSCLC.

II. To assess the pharmacodynamic effects of 5-AZA and entinostat on deoxyribonucleic acid (DNA) methylation, histone acetylation, and gene re-expression in patients with recurrent NSCLC through analysis of blood, sputum and tissue biopsies.

III. To explore the effect of 5-AZA and entinostat on progression-free and overall survival in patients with recurrent advanced non-small cell lung cancer.

IV. To explore the differing response rates and progression-free survivals of two schedules of 5-AZA and entinostat in patients with recurrent advanced non-small cell lung cancer.

OUTLINE: This is a multicenter, phase I, dose-escalation study of azacitidine followed by an open-label, phase II study.

Patients receive azacitidine subcutaneously (SC) on days 1-6 and 8-10 and entinostat orally (PO) on days 3 and 10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 94
• Est. completion date: November 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic or unresectable NSCLC

• Patient must have failed at least one previous chemotherapy regimen

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan

• Life expectancy of greater than 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 (Karnofsky >= 60%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelet count >= 100,000/mcL

• Total bilirubin within normal institutional limits

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

• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73m^2 for patients with creatinine levels above institutional normal

• 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

• Patients who have a major objective response to treatment on this protocol, and who experience progression of disease at least 1 year after completion of protocol consent and therapy, may be re-treated at the previously effective dose and schedule

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients may not be receiving any other investigational agents

• Patients with uncontrolled brain metastases; patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 4 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

• Patients with liver metastases that replace greater than 30% of the liver parenchyma

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat, 5-AZA, mannitol 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; breastfeeding should be discontinued if the mother is treated on this protocol

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Recurrent Non-Small Cell Lung Carcinoma
• Stage IIIA Non-Small Cell Lung Cancer
• Stage IIIB Non-Small Cell Lung Cancer
• Stage IV Non-Small Cell Lung Cancer

Intervention

Drug:
• Azacitidine 30mg/m2
Azacitidine 30mg/m2 subcutaneously (SQ)
• Entinostat
7mg by mouth (PO) on days 3 and 10 of each cycle
• Azacitidine 40mg/m2
Azacitidine 40mg/m2 SQ

Locations

Country	Name	City	State
United States	Johns Hopkins Bayview Medical Center	Baltimore	Maryland
United States	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital	Baltimore	Maryland
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	Sidney Kimmel Cancer Center	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N, Lee B, Tsai S, Delgado IE, Rudek MA, Belinsky SA, Herman JG, Baylin SB, Brock MV, Rudin CM. Combination epigenetic therapy has efficacy in patient — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	(Phase I) Maximum Tolerated Dose (MTD) of Azacitidine When Given Together With Entinostat as Determined by Number of Participants Experiencing Dose-limiting Toxicity (DLT)	DLT is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0	Up to 28 days
Primary	(Phase II) Objective Response Rate After Treatment With Azacitidine and Entinostat as Assessed by Number of Participants With Response After at Least One Cycle of Therapy	Number of participants with progressive disease (PD), stable disease (SD), complete response (CR), or partial response (PR), as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.0), after completing at least one cycle of therapy. Per RECIST 1.0, progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; PR is defined as >=30% decrease in the sum of the longest diameter of target lesions, CR is defined as the disappearance of all target lesions.	Up to 8 years
Secondary	Effect of Entinostat and Azacitidine on DNA Methylation and Response	Number of participants with decrease in DNA methylation ("methylation-signature positive") on Day 10 or Day 29, and either stable disease or objective response (OR) as defined by RECIST 1.0. Per RECIST 1.0, progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; PR is defined as >=30% decrease in the sum of the longest diameter of target lesions, complete response is defined as disappearance of all target lesions; OR=CR+PR.	Baseline and days 10 and 29
Secondary	Major Objective Response After Immediate Subsequent Therapy as Measured by Number of Participants With PR, SD, PD After at Least 1 Cycle of Subsequent Chemotherapy	Number of participants with progressive disease (PD), stable disease (SD), or partial response (PR), as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.0) after at least 1 cycle of subsequent chemotherapy. Per RECIST 1.0, progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; PR is defined as >=30% decrease in the sum of the longest diameter of target lesions.	Up to 8 years
Secondary	Overall Survival	Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.	Up to 1 year
Secondary	Pharmacokinetic Profile of Azacytidine as Measured by Tmax	Time to maximal concentration of azacitidine in the blood.	Day 1
Secondary	Progression-free Survival	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.	Up to 1 year
Secondary	Pharmacokinetic Profile of Azacitidine as Measured by Cmax	Maximal concentration (ng/mL) of azacitidine	Day 1
Secondary	Pharmacokinetic Profile of Azacitidine as Measured by AUC (ng*hr/mL)		Day 1
Secondary	Average Steady State Trough Concentration (ng/mL) of Entinostat		Day 10 and 17
Secondary	Pharmacokinetic Profile of Azacitidine as Measured by Half-life		Day 1