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

Phase 1

Completed

Conditions: 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

Interventions: Drug: Azacitidine 30mg/m2
Drug: Azacitidine 40mg/m2
Drug: Entinostat

Registration Number: NCT00387465

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 94

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I - 40mg/m2 Azacitidine	Azacitidine 40mg/m2	Patients receive azacitidine 40mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Phase II Arm	Azacitidine 40mg/m2	Patients receive azacitidine 40mg/m2 subcutaneously (SQ) on days 1-6 and 8-10 and entinostat 7mg PO on days 3 and 10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Phase I - 30mg/m2 Azacitidine	Azacitidine 30mg/m2	Patients receive Azacitidine 30mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Phase I - 30mg/m2 Azacitidine	Entinostat	Patients receive Azacitidine 30mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Phase I - 40mg/m2 Azacitidine	Entinostat	Patients receive azacitidine 40mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Phase II Arm	Entinostat	Patients receive azacitidine 40mg/m2 subcutaneously (SQ) on days 1-6 and 8-10 and entinostat 7mg PO on days 3 and 10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
(Phase I) Maximum Tolerated Dose (MTD) of Azacitidine When Given Together With Entinostat as Determined by Number of Participants Experiencing Dose-limiting Toxicity (DLT)	Up to 28 days	DLT is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0
(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	Up to 8 years	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.

Secondary Outcome Measures

Name	Time	Method
Effect of Entinostat and Azacitidine on DNA Methylation and Response	Baseline and days 10 and 29	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.
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	Up to 8 years	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.
Overall Survival	Up to 1 year	Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.
Pharmacokinetic Profile of Azacytidine as Measured by Tmax	Day 1	Time to maximal concentration of azacitidine in the blood.
Progression-free Survival	Up to 1 year	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.
Pharmacokinetic Profile of Azacitidine as Measured by Cmax	Day 1	Maximal concentration (ng/mL) of azacitidine
Pharmacokinetic Profile of Azacitidine as Measured by AUC (ng*hr/mL)	Day 1
Average Steady State Trough Concentration (ng/mL) of Entinostat	Day 10 and 17
Pharmacokinetic Profile of Azacitidine as Measured by Half-life	Day 1

Trial Locations

Locations (5): USC Norris Comprehensive Cancer Center
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Los Angeles, California, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
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Baltimore, Maryland, United States
Sidney Kimmel Cancer Center
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San Diego, California, United States
Johns Hopkins Bayview Medical Center
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Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
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Baltimore, Maryland, United States