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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00387465
First received: October 12, 2006
Last updated: July 18, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Recurrent Non-small Cell Lung Cancer
Stage IIIA Non-small Cell Lung Cancer
Stage IIIB Non-small Cell Lung Cancer
Stage IV Non-small Cell Lung Cancer
Drug: entinostat
Drug: azacitidine
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Entinostat in Combination With 5-Azacytidine in Patients With Recurrent Advanced Non-Small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of azacitidine when given together with entinostat, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (phase I) [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
  • Objective response rate after treatment with azacitidine and entinostat using the Response Evaluation Criteria in Solid Tumors (RECIST) (phase II) [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Effect of entinostat and azacitidine on DNA methylation patterns and gene expression [ Time Frame: Baseline and days 10 and 29 ] [ Designated as safety issue: No ]
    The frequency of significant demethylation and acetylation will be summarized across dosing cohorts of azacitidine. The difference between the methylation indices post-and pre-treatment will be compared using paired Student's t-test. Similar analyses will be performed for the acetylation index. Relationships between changes in gene re-expression and clinical response will be assessed using Fisher's exact tests.

  • Pharmacokinetic profile of entinostat and azacitidine [ Time Frame: Baseline, day 1, 10, 15, 17, and 22 ] [ Designated as safety issue: No ]
    A Mann-Whitney U test and logistic regression will be used to evaluate the association between azacitidine or entinostat exposure and methylation and acetylation changes expressed as a categorical variable (i.e.: response or no response). The azacitidine exposure parameters explored will be maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC). The entinostat exposure parameters explored will be Vss.

  • Progression-free survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.

  • Overall survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.

  • Effect of entinostat and azacitidine on enhancing response to subsequent therapy [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 76
Study Start Date: August 2006
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (azacitidine, entinostat)
Patients receive azacitidine SC on days 1-6 and 8-10 and entinostat PO on days 3 and 10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: entinostat
Given PO
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Drug: azacitidine
Given SC
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Other: pharmacological study
Correlative study
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00387465

Locations
United States, California
USC Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
Sidney Kimmel Cancer Center
San Diego, California, United States, 92121
United States, Maryland
Johns Hopkins Bayview Medical Center
Baltimore, Maryland, United States, 21224
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States, 21287
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
Baltimore, Maryland, United States, 21231
Sponsors and Collaborators
Investigators
Principal Investigator: John Wrangle Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00387465     History of Changes
Other Study ID Numbers: NCI-2009-00220, NCI-2009-00220, CDR0000504083, NA_00003114, J0658, 7759, P30CA006973, U01CA070095
Study First Received: October 12, 2006
Last Updated: July 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Azacitidine
Histone Deacetylase Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 23, 2014