PXD101 as Second-Line Therapy in Treating Patients With Malignant Mesothelioma of the Chest That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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This phase II trial is studying how well PXD101 works as second-line therapy in treating patients with malignant mesothelioma of the chest that cannot be removed by surgery. PXD101 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the objective response rate in patients with unresectable malignant pleural mesothelioma (MPM) treated with PXD101. SECONDARY OBJECTIVES: I. Determine the overall survival and time to progression in these patients. II. Assess the toxicities associated with this drug in these patients. III. Perform molecular correlative studies on tumor tissue (optional) and peripheral blood (required) and identify potential predictive markers for response. OUTLINE: Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection during course 1 of treatment for biomarker correlative studies. Fetal hemoglobin (hemoglobin F) levels are measured via reverse transcriptase-polymerase chain reaction as a potential predictive marker for response. After completion of study treatment, patients are followed periodically.

Official Title
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Phase II Study of PXD101 (NSC 726630) as Second-Line Therapy for Treatment of Patients With Malignant Pleural Mesothelioma

Conditions
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Advanced Malignant Mesothelioma, Epithelial Mesothelioma, Recurrent Malignant Mesothelioma, Sarcomatous Mesothelioma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed malignant pleural mesothelioma (MPM) of any of the following subtypes: Epithelial Sarcomatoid Mixed Have received only 1 prior systemic chemotherapy regimen for advanced mesothelioma Prior intrapleural cytotoxic agents (including bleomycin) not considered systemic chemotherapy Patients who are not candidates for combination chemotherapy are eligible even if they have not received prior chemotherapy Unresectable disease Measurable disease, defined as >= 1 unidimensionally measurable lesion >= 20 mm by conventional techniques OR >= 10 mm by spiral CT scan The sole site of measurable disease must not be located within the radiotherapy port No known brain metastases ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100% Life expectancy > 3 months WBC >= 3,000/mm^3 Absolute neutrophil count >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Bilirubin normal AST/ALT =< 2.5 times upper limit of normal Creatinine normal OR creatinine clearance >= 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-barrier contraception for 1 week before, during, and for >= 2 weeks after completion of study treatment No history of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101 No symptomatic congestive heart failure No congestive heart failure related to primary cardiac disease No unstable angina pectoris No cardiac arrhythmia No condition requiring anti-arrhythmic therapy No uncontrolled hypertension No myocardial infarction within the past 6 months No ischemic or severe valvular heart disease No ongoing or active infection No marked baseline prolongation of QT/QTc interval No repeated QTc interval > 500 msec No long QT syndrome No other significant cardiovascular disease No other uncontrolled intercurrent illness No psychiatric illness or social situation that would preclude study compliance Recovered from prior therapy No prior valproic acid or other known histone deacetylase (HDAC) inhibitor More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) More than 3 weeks since prior radiation therapy No concurrent medication that may cause torsade de pointes No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational agents No other concurrent anticancer agents or therapies

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 (belinostat)<br>Patients receive PXD101 IV at 1000 mg/m2 over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: belinostat<br>* Given IV<br>* Other names: PXD101;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 |
| --- | --- | --- |
| Objective Tumor Response Rate According to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT, MRI or X-ray: 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 | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier. | Up to 3 years | 
| Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Up to 3 years | 
| Toxicity Profile | Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen. Toxicities table summarizes the observed incidence by severity and type of toxicity for toxicities that are related to treatment and greater than grade 1. Adverse events assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. | Up to 3 years | 
| Apoptosis by TUNEL Assay | Summarized with contingency tables or scatterplots, and with quantitative measures of agreement. | At baseline | 
| Histone Acetylation by IHC and Western Blotting | Summarized with contingency tables or scatterplots, and with quantitative measures of agreement. | At baseline and at 4 hours after last dose of PXD101 on day 5 |