Vorinostat, Paclitaxel, and Radiation Therapy in Treating Patients Unable to Tolerate Cisplatin With Stage III Non-Small Lung Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of vorinostat when given together with paclitaxel and radiation therapy and to see how well it works in treating patients unable to tolerate cisplatin with stage III non-small cell lung cancer (NSCLC) that cannot be removed by surgery. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with paclitaxel and radiation therapy may kill more tumor cells

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of vorinostat when administered in combination with paclitaxel and thoracic radiation therapy in patients with locally advanced NSCLC. SECONDARY OBJECTIVES: I. To assess the safety and toxicity of vorinostat when administered in combination with paclitaxel and thoracic radiation therapy in patients with locally advanced NSCLC. II. To determine the radiological response rate, by computed tomography (CT) scan, of vorinostat when administered in combination with paclitaxel and thoracic radiation therapy in patients with locally advanced NSCLC. III. To describe the progression free survival (PFS) and overall survival (OS) of this regiment over 3 years of follow up. OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study. Patients receive vorinostat orally (PO) once daily (QD), 5 days a week and paclitaxel intravenously (IV) over 1 hour once a week. Patients also undergo radiation therapy QD, 5 days a week. Treatment repeats every week for 7 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, 12 weeks, every 3 months for 2 years, and then every 6 months for 1 year.

Official Title
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Phase I/II Clinical Trial Evaluating the Use of Vorinostat Combined With Paclitaxel and Radiotherapy in Patients With Inoperable Stage III Non-Small Cell Lung Cancer Unable to Tolerate Cisplatin

Conditions
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Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: vorinostat
* Drug: paclitaxel
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven diagnosis of NSCLC Inoperable Stage IIIA or IIIB (excluding malignant pleural effusion) disease according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Sixth edition (2002) At least one site of measurable disease, as defined by the modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Inability to tolerate full dose cisplatin as defined by: Creatinine clearance less than 50ml/min Greater than grade 2 sensory hearing loss (as defined by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] criteria v3.0 adverse event term Hearing: Patients without baseline audiogram and not enrolled in a monitoring program) Performance status >= 2 Age >= 75 years Cardiac history, such as myocardial infarction within 6 months, angina, or heart disease as defined by the New York Heart Association (NYHA) Class III or IV Any other comorbid disease or condition that would increase the risk of toxicity of cisplatin therapy Female patient is either post menopausal, free from menses for >= 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study Female patient of childbearing potential has a negative serum pregnancy test beta-human chorionic gonadotropin (hCG) within 7 days prior to receiving the first dose of vorinostat Male patient agrees to use an adequate method of contraception for the duration of the study Absolute neutrophil count (ANC) >= 1,500/mcL Platelets >= 100,000/mcL Hemoglobin >= 9 g/dL Prothrombin Time or International Normalized Ratio (INR) =< 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation Partial thromboplastin time (PTT) =< 1.2 times the ULN unless the patient is receiving therapeutic anticoagulation Potassium levels: Normal limits Magnesium levels: Normal limits Calculated creatinine clearance >= 20 mL/min Serum total bilirubin =< 1.5 X ULN Aspartate aminotransferase (AST) (serum glutamate oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN Alkaline Phosphatase =< 2.5 X ULN Patient, or the patient's legal representative, has voluntarily agreed to participate by giving written informed consent Patient has a life expectancy of at least 12 weeks Patient is available for periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study Exclusion Criteria: Patient who has had chemotherapy, radiotherapy, or biological therapy for NSCLC within 5 years prior to initial dosing with study drug(s) Symptomatic neuropathy (>= grade 2) Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug(s) Patient had prior treatment with an histone deacetylases (HDAC) inhibitor (e.g., romidespsin [Depsipeptide, NSC-630176], entinostat [MS 275], dacinostat [LAQ-824], belinostat [(PXD-101]), panobinostat [LBH589], mocetinostat [MGCD0103], CRA024781, etc); patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study; patients who have received such compounds for other indications, e.g., valproic acid for epilepsy, may enroll after a 30-day washout period Patient has known hypersensitivity to the components of study drug or its analogs or paclitaxel NYHA Class III or IV congestive heart failure, myocardial infarction within the previous 6 months, QTc > 0.47 seconds, or uncontrolled arrhythmia Patient is pregnant or breast feeding, or expecting to conceive or father children within the projected duration of the study Patient with a currently active second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled; patients are not considered to have a currently active malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for > 5 years or are considered by their physician to be at less than 30% risk of relapse Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study or is not in the best interest of the patient to participate

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 (vorinostat with paclitaxel and radiotherapy)<br>Patients receive vorinostat PO QD, 5 days a week and paclitaxel IV over 1 hour once a week. Patients also undergo radiation therapy QD, 5 days a week. Treatment repeats every week for 7 courses in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* Given PO<br>* Other names: Zolinza;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Radiation: radiation therapy<br>* Undergo radiation therapy<br>* Other names: therapy, radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of Vorinostat When Administered in Combination With Paclitaxel and Radiotherapy Therapy as Assessed by NCI Common Toxicity Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I) | Defined as the highest dose level at which no more than 1 of 6 patients experiences dose-limiting toxicity (DLT). Toxicity was graded according to the National Institutes of Health Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. A DLT was defined as any Grade 3 or higher non-hematologic adverse event with the exception of alopecia, fatigue, or anorexia. Nausea and/or vomiting that persisted > 48 hours despite optimal medical management at grade 3 or higher was considered a DLT. Hematologic dose-limiting toxicity was defined as either: Grade 4 neutropenia lasting for ≥ 7 days in duration, Grade > 3 febrile neutropenia with/without infection, Grade 4 thrombocytopenia or Grade 5 hematologic toxicity. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological Response Rate as Assessed by CT | Count of participants with stable disease or partial response. Patients were evaluated for treatment response per RECIST criteria (version 1.0). | 12 weeks post-treatment, then every 3 months for 2 years, and then every 6 months for a year thereafter | 
| Duration of Response |  | Up to 3 years | 
| Progression-free Survival | Kaplan-Meier estimate. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). | 1 year | 
| Overall Survival | Kaplan-Meier estimate | 1 year | 
| Safety and Toxicity of Vorinostat at the MTD as Assessed by NCI CTCAE Version 3.0 | Count of participants with a grade 3 or higher toxicity. Toxicities were assessed using the NCI CTCAE (v3.0). Grade 3 or higher toxicities were considered worse. | Weekly during treatment, 30 days post-treatment, and 12 weeks post-treatment |