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

A Randomized Phase II Trial of Cytotoxic Chemotherapy With or Without Epigenetic Priming in Patients With Advanced Non-Small Cell Lung Cancer

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01935947

Enrollment

Registered

2013-09-05

Start date

2013-05-31

Completion date

2017-04-30

Last updated

2018-07-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

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

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.

Detailed description

PRIMARY OBJECTIVES: I. Percentage of patients progression-free at 6 months from time of randomization. SECONDARY OBJECTIVES: I. Progression-free survival (PFS). II. Overall survival (OS). OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM A: 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 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 intravenously (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. ARM B: 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. ARM C: Patients receive chemotherapy of the treating oncologist's choice as in Arm A. After completion of treatment, patients are followed up every 3-6 months for 24 months and then yearly thereafter.

Interventions

DRUGAzacitidine

Given SC

DRUGDocetaxel

Given IV

DRUGEntinostat

Given PO

DRUGGemcitabine Hydrochloride

Given IV

DRUGIrinotecan Hydrochloride

Given IV

OTHERLaboratory Biomarker Analysis

Correlative studies

DRUGPemetrexed Disodium

Given IV

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* 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

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 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

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients Progression-free at 6 Months From the Time of Randomization	At 6 months	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.

Secondary

Measure	Time frame	Description
Overall Survival (OS)	From the time of enrollment to trial until death, assessed up to 2 years	—
Progression Free Survival	up to 2 years	From the time of randomization until radiologic or clinical progression is noted, assessed up to 2 years.

Other

Measure	Time frame	Description
Genome-wide Techniques, Including Expression Array and Methylation Array	After 1 month of therapy	Expression array and methylation array will be compared to response.
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	—

Countries

United States

Participant flow

Pre-assignment details

There were seven screen failures.

Participants by arm

Arm	Count
Arm I (Azacitidine, Entinostat, Chemotherapy) 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 then patients receive chemotherapy. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	4
Arm II (Azacitidine, Entinostat, Chemotherapy) Patients receive azacitidine PO on days 1-21 and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 2 courses, and then patients receive chemotherapy as in Arm A.	4
Arm III (Chemotherapy) Patients receive chemotherapy of the treating oncologist's choice as in Arm A.	2
Total	10

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	0	2	0
Overall Study	Death	1	0	0
Overall Study	Diease Progression	2	2	2

Baseline characteristics

Characteristic	Arm I (Azacitidine, Entinostat, Chemotherapy)	Arm II (Azacitidine, Entinostat, Chemotherapy)	Arm III (Chemotherapy)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	3 Participants	2 Participants	0 Participants	5 Participants
Age, Categorical Between 18 and 65 years	1 Participants	2 Participants	2 Participants	5 Participants
Age, Continuous	63 years STANDARD_DEVIATION 12.6	62 years STANDARD_DEVIATION 8.4	54 years STANDARD_DEVIATION 2	60 years STANDARD_DEVIATION 4
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	4 Participants	2 Participants	10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants	2 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	0 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	2 Participants	1 Participants	6 Participants
Region of Enrollment United States	4 participants	4 participants	2 participants	10 participants
Sex: Female, Male Female	0 Participants	3 Participants	0 Participants	3 Participants
Sex: Female, Male Male	4 Participants	1 Participants	2 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	1 / 4	1 / 4	0 / 2
other Total, other adverse events	4 / 4	4 / 4	2 / 2
serious Total, serious adverse events	2 / 4	4 / 4	1 / 2

Outcome results

Primary

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.

Time frame: At 6 months