A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- Azacitidine 30mg/m2
- Conditions
- Recurrent Non-Small Cell Lung Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 94
- Locations
- 5
- Primary Endpoint
- (Phase I) Maximum Tolerated Dose (MTD) of Azacitidine When Given Together With Entinostat as Determined by Number of Participants Experiencing Dose-limiting Toxicity (DLT)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Phase I - 30mg/m2 Azacitidine
Patients receive Azacitidine 30mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Intervention: Azacitidine 30mg/m2
Phase I - 30mg/m2 Azacitidine
Patients receive Azacitidine 30mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Intervention: Entinostat
Phase I - 40mg/m2 Azacitidine
Patients receive azacitidine 40mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Intervention: Entinostat
Phase I - 40mg/m2 Azacitidine
Patients receive azacitidine 40mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Intervention: Azacitidine 40mg/m2
Phase II Arm
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.
Intervention: Entinostat
Phase II Arm
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.
Intervention: Azacitidine 40mg/m2
Outcomes
Primary Outcomes
(Phase I) Maximum Tolerated Dose (MTD) of Azacitidine When Given Together With Entinostat as Determined by Number of Participants Experiencing Dose-limiting Toxicity (DLT)
Time Frame: 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
Time Frame: 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 Outcomes
- Effect of Entinostat and Azacitidine on DNA Methylation and Response(Baseline and days 10 and 29)
- 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)
- Overall Survival(Up to 1 year)
- Pharmacokinetic Profile of Azacytidine as Measured by Tmax(Day 1)
- Progression-free Survival(Up to 1 year)
- Pharmacokinetic Profile of Azacitidine as Measured by Cmax(Day 1)
- 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)