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

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ClinicalTrials.gov Identifier: NCT00387465
Recruitment Status : Completed
First Posted : October 13, 2006
Results First Posted : May 9, 2019
Last Update Posted : May 9, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
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 Drug: Azacitidine 30mg/m2 Drug: Entinostat Drug: Azacitidine 40mg/m2 Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 94 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : August 2006
Actual Primary Completion Date : May 2014
Actual Study Completion Date : November 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Azacitidine

Arm Intervention/treatment
Experimental: Phase I - 30mg/m2 Azacitidine
Patients receive Azacitidine 30mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Drug: Azacitidine 30mg/m2
Azacitidine 30mg/m2 subcutaneously (SQ)
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • AZACITIDINE
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Drug: Entinostat
7mg by mouth (PO) on days 3 and 10 of each cycle
Other Names:
  • HDAC inhibitor SNDX-275
  • MS 27-275
  • MS-275
  • SNDX-275

Experimental: Phase I - 40mg/m2 Azacitidine
Patients receive azacitidine 40mg/m2 SQ and entinostat 7mg PO on days 3 and 10 of each cycle.
Drug: Entinostat
7mg by mouth (PO) on days 3 and 10 of each cycle
Other Names:
  • HDAC inhibitor SNDX-275
  • MS 27-275
  • MS-275
  • SNDX-275

Drug: Azacitidine 40mg/m2
Azacitidine 40mg/m2 SQ
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • AZACITIDINE
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Experimental: 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.
Drug: Entinostat
7mg by mouth (PO) on days 3 and 10 of each cycle
Other Names:
  • HDAC inhibitor SNDX-275
  • MS 27-275
  • MS-275
  • SNDX-275

Drug: Azacitidine 40mg/m2
Azacitidine 40mg/m2 SQ
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • AZACITIDINE
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza




Primary Outcome Measures :
  1. (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

  2. (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 Outcome Measures :
  1. Effect of Entinostat and Azacitidine on DNA Methylation and Response [ Time Frame: 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.

  2. 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 [ Time Frame: 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.

  3. Overall Survival [ Time Frame: Up to 1 year ]
    Determined by the method determined by Kaplan and Meier. 95% confidence intervals will be estimated.

  4. Pharmacokinetic Profile of Azacytidine as Measured by Tmax [ Time Frame: Day 1 ]
    Time to maximal concentration of azacitidine in the blood.

  5. Progression-free Survival [ Time Frame: 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.

  6. Pharmacokinetic Profile of Azacitidine as Measured by Cmax [ Time Frame: Day 1 ]
    Maximal concentration (ng/mL) of azacitidine

  7. Pharmacokinetic Profile of Azacitidine as Measured by AUC (ng*hr/mL) [ Time Frame: Day 1 ]
  8. Average Steady State Trough Concentration (ng/mL) of Entinostat [ Time Frame: Day 10 and 17 ]
  9. Pharmacokinetic Profile of Azacitidine as Measured by Half-life [ Time Frame: Day 1 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00387465


Locations
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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
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
Baltimore, Maryland, United States, 21231
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: John Wrangle Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Publications of Results:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00387465     History of Changes
Other Study ID Numbers: NCI-2009-00220
NCI-2009-00220 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000504083 ( Other Identifier: Clinical Data Repository )
NA_00003114 ( Other Identifier: Johns Hopkins IRB )
J0658 ( Other Identifier: SKCCC )
7759 ( Other Identifier: CTEP )
P30CA006973 ( U.S. NIH Grant/Contract )
U01CA070095 ( U.S. NIH Grant/Contract )
First Posted: October 13, 2006    Key Record Dates
Results First Posted: May 9, 2019
Last Update Posted: May 9, 2019
Last Verified: April 2019

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