Suberoylanilide Hydroxamic Acid in Treating Patients With Stage IIIB, Stage IV, or Recurrent Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well suberoylanilide hydroxamic acid works in treating patients with stage IIIB, stage IV, or recurrent non-small cell lung cancer. Drugs used in chemotherapy, such as suberoylanilide hydroxamic acid, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Suberoylanilide hydroxamic acid may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the response of non-small cell lung cancer to SAHA in the second line setting by applying RECIST criteria. SECONDARY OBJECTIVES: I. To estimate the time to progression and overall survival in this patient population. II. To examine the toxicity profile of SAHA. TERTIARY OBJECTIVES: I. To evaluate the molecular activity of SAHA by evaluating its effect on histone acetylation, upregulation of target genes, generation of reactive oxygen species, apoptosis and correlation with P53 status. II. To explore gene expression profiles that predict response to SAHA. OUTLINE: This is a multicenter study. Patients receive oral suberoylanilide hydroxamic acid once daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 1 month and then every 3 months for 1 year or until disease progression.

Official Title
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A Phase II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Patients With Relapsed Non-small Cell Lung Cancer

Conditions
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Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: vorinostat
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed non-small cell lung carcinoma, Stage IV (distant metastases), stage IIIB with malignant pleural effusion, or recurrent disease 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 CT scan Prior therapy: no more than 1 prior cytotoxic chemotherapy regimen for their Stage IIIB/IV or recurrent disease; no previous irradiation to the only area of measurable disease, unless that site had subsequent progression of disease; radiation therapy must be completed at least 3 weeks prior to initiating study drug Stage IV patients with brain metastases are eligible providing the brain metastases are clinically and radiologically stable 4 weeks after treatment with surgery and/or radiation therapy, and they are not taking steroids Life expectancy greater than 3 months ECOG performance status 0 or 1 (Karnofsky >= 70%) Patients must have normal organ and marrow function as defined below: Leukocytes >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within normal institutional limits AST(SGOT)/ALT(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 Peripheral neuropathy =< grade 1 Caution needs to be exercised when using SAHA with medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of SAHA; since grapefruit juice is known to interact with the CYP450 enzymes, it is recommended that patients abstain from consuming grapefruit, grapefruit juice, and other grapefruit containing products during this study The effects of SAHA on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because HDAC inhibitors are known to be teratogenic, 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 should not have taken valproic acid, another histone deacetylase inhibitor, for at least 2 weeks prior to enrollment Exclusion Criteria: Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 3 weeks prior to entering the study Patients may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to SAHA Any other active malignancy in the past 5 years except non-melanoma skin cancers 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 Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SAHA, breastfeeding should be discontinued if the mother is treated with SAHA HIV-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with SAHA; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

Ages Eligible for Study
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Minimum Age: 19 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 (vorinostat)<br>Patients receive oral suberoylanilide hydroxamic acid once daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* Given PO<br>* Other names: Zolinza;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Per RECIST Criteria | Per Response Evaluation Criteria In Solid Tumors and assessed by CT: Complete Response(CR), Disappearance of all target lesions; Partial Response(PR),>=30% decrease in the sum of the longest diameter of target lesions; Overall Response(OR) = CR + PR. | Time from treatment initiation until the end of treatment. The median number of cycles was 3 (range 1-27) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to progression per Response Evaluation Criteria In Solid Tumors and assessed by CT: Complete Response(CR), Disappearance of all target lesions; Partial Response(PR),>=30% decrease in the sum of the longest diameter of target lesions; Overall Response(OR) = CR + PR. | From start of treatment to progression (average was 3.7 months) | 
| Overall Survial | Overall survial of subjects from the start of treatment to the time of death | From treatment start to time of death | 
| Toxicity | Number of participants experiencing adverse events possibly related to SAHA from first dose of treatment until 30 days from the last dose of treatment. | From first dose of treatment until 30 days from the last dose of treatment |