Vorinostat, Carboplatin, and Paclitaxel in Treating Patients With Advanced or Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying carboplatin, paclitaxel, and vorinostat to see how well they work compared with carboplatin, paclitaxel, and a placebo in treating patients with stage III or stage IV non-small cell lung cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carboplatin and paclitaxel together with vorinostat is more effective than giving carboplatin and paclitaxel together with a placebo in treating non-small cell lung cancer

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the response rate associated with the combination of vorinostat, carboplatin, paclitaxel versus carboplatin, paclitaxel and placebo for patients with previously untreated, advanced NSCLC. SECONDARY OBJECTIVES: I. To determine the time to progression and overall survival for the two regimens. II. To assess the safety profile of the regimen of vorinostat, carboplatin and paclitaxel for patients with advanced NSCLC. III. To understand mechanistic aspects of drug effect by conducting correlative science studies on peripheral blood, archived tumor tissue, and paired biopsies in consenting patients. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to gender and brain metastasis (present vs absent). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral vorinostat (SAHA) once daily on days 1-14 and paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 3. Arm II: Patients receive an oral placebo once daily on days 1-14 and paclitaxel and carboplatin as in arm l. In both arms, treatment repeats every 21 days for 4-6 courses in the absence of disease progression or unacceptable toxicity.

Official Title
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Randomized Phase II Study of Vorinostat or Placebo in Combination With Carboplatin and Paclitaxel for Patients With Advanced or Metastatic 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
* Drug: paclitaxel
* Drug: carboplatin
* Other: placebo
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed stage IIIB (with malignant pleural pericardial effusion) or stage IV non-small cell lung cancer No prior chemotherapy for advanced or metastatic disease ECOG performance status 0 or 1 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 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 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 Vorinostat can cause fetal harm when administered to a pregnant woman; there are no adequate and well-controlled studies in pregnant women; if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 3 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 untreated brain metastases should be excluded from this clinical trial; however, patients who have stable brain disease (should be off corticosteroids) at least 3 weeks after completion of appropriate therapy are eligible Prior or current use of valproic acid, a HDAC inhibitor Peripheral neuropathy of severity greater than grade 1 Known history of allergic reactions to paclitaxel Prior therapy with paclitaxel Inability to take oral medications on a continuous basis 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 because vorinostat is an HDAC inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with vorinostat, breastfeeding should be discontinued if the mother is treated with vorinostat; these potential risks may also apply to other agents used in this study HIV-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with vorinostat; 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 antiretroviral therapy when indicated

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (vorinostat, paclitaxel, carboplatin)<br>Patients receive oral vorinostat (SAHA) at 400 mg once daily on days 1-14 and paclitaxel IV 200 mg/m2 over 3 hours and carboplatin IV dosed to achieve an area under the concentration versus time curve of 6 mg/mLXmin over 30 minutes on day 3. | Drug: vorinostat<br>* Given PO<br>* Other names: Zolinza;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Active Comparator: Arm II (placebo, paclitaxel, carboplatin)<br>Patients receive an oral placebo once daily on days 1-14 and paclitaxel and carboplatin as in arm l. | Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Other: placebo<br>* Given PO<br>* Other names: PLCB;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 Rate | Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). Patients with confirmed CR or PR according to the RECIST criteria were considered to have responded to treatment. | Assessed every two cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Evaluated using the Kaplan-Meier method. Compared between arms using the log-rank test. | Up to 1 year | 
| Overall Survival | Evaluated using the Kaplan-Meier method. Compared between arms using the log-rank test. | Up to 1 year |