Azacitidine in Treating Patients With Previously Treated Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This phase II clinical trial is studying how well azacitidine works in treating patients with previously treated advanced non-small cell lung cancer. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the ability of 5-azacytidine to cause DNA hypomethylation and re-expression of silenced tumor suppressor genes when stratified for high or low expression of mir29a, b, and c. SECONDARY OBJECTIVES: I. To compare the molecular studies (mir29 expression and tumor suppressor gene methylation) between archival tissue, fresh biopsy pre-treatment samples, and post-treatment fresh samples. II. To determine the overall response rate by CT (RECIST 1.1 criteria) and PET (EORTC PET response criteria), PFS, and OS of patients treated with azacytidine in the second- or third-line setting. III. To correlate the blood microRNA profiles (and changes in microRNA profiles) with response to azacytidine. OUTLINE: Patients receive azacitidine subcutaneously on days 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tissue and blood sample collection at baseline and periodically during study treatment for correlative studies. After completion of study treatment, patients are followed up for 12 weeks.

Official Title
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Pilot Phase II Study of 5-Azacytidine in Previously Treated Patients With Advanced NSCLC

Conditions
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Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Non-Small Cell Cancer AJCC v7

Intervention / Treatment
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* Drug: Azacitidine
* Other: Diagnostic Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced (stage 4 or recurrent) NSCLC, not eligible for any curative intent treatment Tumor must be histologically or cytologically confirmed Measurable disease (as defined by RECIST criteria) Patients may have up to two (and at least one) prior cytotoxic regimens in the metastatic setting Prior adjuvant chemotherapy following resection or definitive chemo-radiation for patients with locally advanced disease is not included in this Allowable systemic therapy in the metastatic setting includes 2 cytotoxic regimens and erlotinib and/or other non-cytotoxic drugs (i.e., erlotinib, sorafenib, and other tyrosine kinase inhibitors do not count as a cytotoxic regimen) Prior adjuvant therapy or definitive chemo-radiation is allowed if completed > six months before the onset of first-line therapy in the metastatic setting - in this setting, adjuvant or definitive chemo-radiation will not count as one of the two cytotoxic regimens; if however, the patient relapses within six months from completion of adjuvant or definitive chemoradiation, then this therapy will be considered the first-line cytotoxic therapy In the unusual circumstance where patients receive adjuvant therapy following resection of oligo-metastatic disease (for example brain metastasis and lung primary resections) and the treating physician decides to administer chemotherapy following all surgery, this will be considered adjuvant therapy and the same rules as noted above will apply for initiation of first-line systemic therapy No patients with uncontrolled brain metastases or leptomeningeal disease Patients with controlled brain metastases are allowed ECOG performance status 0-2 Absolute neutrophil count ≥ 1.5 x 10^9/L Platelets ≥ 100,000 x 10^9/L Hemoglobin ≥ 9.0 gm/100 mL Total bilirubin ≤ 1.5 mg/dL AST and ALT ≤ 2.5 x ULN Creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance > 50 mL/min No patients who are pregnant Women of childbearing potential must have a negative pregnancy test The patient must be willing to use adequate contraception for the duration of study treatment and up to four weeks following the last dose of drug Archival diagnostic material sufficient for microRNA evaluation/assessment is preferred, though optional The presence of archival material will not preclude the need for pre and post treatment biopsies Willing to undergo biopsy pre-treatment and following first cycle Biopsy may be from any accessible site (primary or metastatic) No known HIV or hepatitis B or C (though testing for this is not required) No uncontrolled intercurrent illness including, but not limited to: Symptomatic CHF Unstable angina pectoris Serious cardiac arrhythmia Serious infection Psychiatric illness or social situations that would limit compliance with study requirements No patients who have significant psychiatric illness that, in the opinion of the principal investigator, would prevent adequate informed consent or render therapy unsafe Patients may not have had a prior invasive malignancy except for adequately treated non-melanoma cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 2 years For example, a stage 1 (T1c) prostate cancer 2 years prior to a diagnosis of NSCLC would not be exclusionary, however, a metastatic prostate cancer currently receiving hormonal or chemotherapy would be excluded No other concurrent palliative radiotherapy Recovered from prior surgery, radiation, or chemotherapy to ≤ grade 2 toxicity Palliative radiation or surgical procedures (for example, endobronchial therapy) is allowed, but must have been completed > 2 weeks prior to starting treatment No other investigational or commercial agents or therapies may be administered with the intent to treat the patient's malignancy No other concurrent investigational therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (azacitidine)<br>Patients receive azacitidine subcutaneously on days 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Azacitidine<br>* Given subcutaneously<br>* Other names: Vidaza;Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DNA Hypomethylation and Re-expression of Silenced Tumor Suppressor Genes When Stratified for Low or High Expression of mir29 | The change in mean methylation of the genes between the patients with a low mir29 and a high mir29 expression will be evaluated by a two-sample t-test. Secondary analyses include a multivariate regression where all 5 changes in methylation will be regressed on mir29 expression (low vs. high) and adjusted for patient demographic and clinical attributes at baseline. | Up to 12 weeks after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Analyzed using a Kaplan-Meier methods. | From the day of initial treatment until death (from any cause), assessed up to 12 weeks after completion of study treatment | 
| Progression-free Survival | Analyzed using a Kaplan-Meier methods. | From the day of initial treatment until documented disease progression (per PET) or death, assessed up to 12 weeks after completion of study treatment |