Azacitidine and Entinostat Before Chemotherapy in Treating Patients With Advanced Non-small Cell Lung Cancer

NCT01935947 | Terminated Phase 2 Results DMC

• 5 other identifiers: NCI-2013-00949NA_00081948/J1309NA_000819489253P30CA006973
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 5

Brief Summary

This randomized phase II trial studies how well azacitidine and entinostat before chemotherapy works in treating patients with non-small cell lung cancer that has spread to other places in the body. Drugs used in chemotherapy, such as azacitidine, irinotecan hydrochloride, gemcitabine hydrochloride, docetaxel, and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine and entinostat before chemotherapy may work better in treating patients with non-small cell lung cancer.

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

Outcome Measures

Primary Outcomes (1)

• Percentage of Patients Progression-free at 6 Months From the Time of Randomization

  The final analysis will be by Fisher's Exact test, with percentage of patients who have not progressed as the outcome variable. Using Fisher's Exact test for analysis with 55 patients per treatment group will provide 88% power to detect an increase from 40% (chemotherapy alone) to 65% (epigenetic therapy followed by chemotherapy) in the number of patients who are progression free at six months.

  At 6 months

Secondary Outcomes (2)

• Overall Survival (OS)

  From the time of enrollment to trial until death, assessed up to 2 years

• Progression Free Survival

  up to 2 years

Other Outcomes (3)

• Genome-wide Techniques, Including Expression Array and Methylation Array

  After 1 month of therapy

• Predictive and Prognostic Value of the Previously Defined Epigenetic Signature, Comprised of Promoter Methylation Analysis of 4 Target Genes

  After 1 month of therapy

• Response to Therapy Compared to Genetic and Epigenetic Factors and Tested for Association

  After 1 month of therapy

Study Arms (3)

Arm I (azacitidine, entinostat, chemotherapy)

EXPERIMENTAL

Patients receive azacitidine SC on days 1-6 and 8-10 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice comprising irinotecan hydrochloride IV on day 1, docetaxel IV on day 1, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine; Drug: Docetaxel; Drug: Entinostat; Drug: Gemcitabine Hydrochloride; Drug: Irinotecan Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Pemetrexed Disodium

Arm II (azacitidine, entinostat, chemotherapy)

EXPERIMENTAL

Patients receive azacitidine PO on days 1-21 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or progressive disease receive chemotherapy of the treating oncologist's choice as in Arm A.

Drug: Azacitidine; Drug: Docetaxel; Drug: Entinostat; Drug: Gemcitabine Hydrochloride; Drug: Irinotecan Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Pemetrexed Disodium

Arm III (chemotherapy)

ACTIVE COMPARATOR

Patients receive chemotherapy of the treating oncologist's choice as in Arm A.

Drug: Docetaxel; Drug: Gemcitabine Hydrochloride; Drug: Irinotecan Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Pemetrexed Disodium

Interventions

Azacitidine DRUG

Given SC

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Arm I (azacitidine, entinostat, chemotherapy)

Docetaxel DRUG

Given IV

Also known as: Docecad, RP56976, Taxotere, Taxotere Injection Concentrate

Arm I (azacitidine, entinostat, chemotherapy); Arm II (azacitidine, entinostat, chemotherapy); Arm III (chemotherapy)

Entinostat DRUG

Given PO

Also known as: HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275

Arm I (azacitidine, entinostat, chemotherapy); Arm II (azacitidine, entinostat, chemotherapy)

Gemcitabine Hydrochloride DRUG

Given IV

Also known as: dFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011

Arm I (azacitidine, entinostat, chemotherapy); Arm II (azacitidine, entinostat, chemotherapy); Arm III (chemotherapy)

Irinotecan Hydrochloride DRUG

Given IV

Also known as: Campto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440E

Arm I (azacitidine, entinostat, chemotherapy); Arm II (azacitidine, entinostat, chemotherapy); Arm III (chemotherapy)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (azacitidine, entinostat, chemotherapy); Arm II (azacitidine, entinostat, chemotherapy); Arm III (chemotherapy)

Pemetrexed Disodium DRUG

Given IV

Also known as: Alimta, LY231514, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt

Arm I (azacitidine, entinostat, chemotherapy); Arm II (azacitidine, entinostat, chemotherapy); Arm III (chemotherapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically proven non-small cell lung cancer; tumor tissue must be available from all patients prior to initiation of protocol therapy, either from original diagnostic biopsy, or biopsy performed prior to initiation of protocol therapy
• 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 for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Patients must have received 1 prior platinum containing doublet regardless of mutation status
• Patients with targetable mutation i.e. epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK), must have been treated with at least 1 prior tyrosine kinase inhibitor (TKI)
• Prior immunotherapy is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky \>= 70%)
• Life expectancy of greater than 12 weeks
• Leukocytes \>= 3,000/mcL
• Absolute neutrophil count \>= 1,500/mcL
• Platelets \>= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transferase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transferase \[SGPT\]) =\< 2.5 X institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^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 she or her partner is participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

You may not qualify if:

• 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 who are 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 may be treated with steroids as clinically indicated
• 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, azacitidine, mannitol, irinotecan, docetaxel, pemetrexed, or gemcitabine, or other agents used in the study
• Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, New York Heart Association (NYHA) class 3-4 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

USC Norris Oncology/Hematology-Newport Beach

Newport Beach, California, 92663, United States

Location

Johns Hopkins Bayview Medical Center

Baltimore, Maryland, 21224, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Azacitidine; Docetaxel; entinostat; Gemcitabine; Irinotecan; Pemetrexed

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Deoxycytidine; Camptothecin; Alkaloids; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Limitations and Caveats

Low recruitment lead to slow accrual. Not having enough patients on the trial and high disease progression lead to closing the study.

Results Point of Contact

• Title: Gary Rosner
• Organization: Johns Hopkins University

grosner1@jhmi.edu

410-955-4884

Study Officials

• Julie Brahmer

  Johns Hopkins University/Sidney Kimmel Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2013
• First Posted: September 5, 2013
• Study Start: May 1, 2013
• Primary Completion: April 1, 2017
• Study Completion: April 1, 2017
• Last Updated: July 27, 2018
• Results First Posted: July 27, 2018

Record last verified: 2018-06

Locations

US (5)