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

NCT ID: NCT00387465

Last Updated: 2019-05-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 94 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2014-11-30

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase I - 30mg/m2 Azacitidine

Patients receive Azacitidine 30mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.

Group Type: EXPERIMENTAL

Azacitidine 30mg/m2

Intervention Type: DRUG

Azacitidine 30mg/m2 subcutaneously (SQ)

Entinostat

Intervention Type: DRUG

7mg by mouth (PO) on days 3 and 10 of each cycle

Phase I - 40mg/m2 Azacitidine

Patients receive azacitidine 40mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.

Group Type: EXPERIMENTAL

Entinostat

Intervention Type: DRUG

7mg by mouth (PO) on days 3 and 10 of each cycle

Azacitidine 40mg/m2

Intervention Type: DRUG

Azacitidine 40mg/m2 SQ

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.

Group Type: EXPERIMENTAL

Entinostat

Intervention Type: DRUG

7mg by mouth (PO) on days 3 and 10 of each cycle

Azacitidine 40mg/m2

Intervention Type: DRUG

Azacitidine 40mg/m2 SQ

Interventions

Azacitidine 30mg/m2

Azacitidine 30mg/m2 subcutaneously (SQ)

Intervention Type: DRUG

Entinostat

7mg by mouth (PO) on days 3 and 10 of each cycle

Intervention Type: DRUG

Azacitidine 40mg/m2

Azacitidine 40mg/m2 SQ

Intervention Type: DRUG

Other Intervention Names

5 AZC; 5-AC; 5-Azacytidine; 5-AZC; AZACITIDINE; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; HDAC inhibitor SNDX-275; MS 27-275; MS-275; SNDX-275; 5 AZC; 5-AC; 5-Azacytidine; 5-AZC; AZACITIDINE; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza

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
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John Wrangle

Role: PRINCIPAL_INVESTIGATOR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Locations

USC Norris Comprehensive Cancer Center

Los Angeles, California, United States

Sidney Kimmel Cancer Center

San Diego, California, United States

Johns Hopkins Bayview Medical Center

Baltimore, Maryland, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

Countries

United States

References

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 patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011 Dec;1(7):598-607. doi: 10.1158/2159-8290.CD-11-0214. Epub 2011 Nov 9.

Reference Type: RESULT

PMID: 22586682 (View on PubMed)

Other Identifiers

NCI-2009-00220

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000504083

Identifier Type: OTHER

Identifier Source: secondary_id

NA_00003114

Identifier Type: OTHER

Identifier Source: secondary_id

J0658

Identifier Type: OTHER

Identifier Source: secondary_id

7759

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA006973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01CA070095

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2009-00220

Identifier Type: -

Identifier Source: org_study_id