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

Phase 2

Completed

Conditions: Epithelial Mesothelioma
Sarcomatous Mesothelioma
Recurrent Malignant Mesothelioma
Advanced Malignant Mesothelioma

Interventions: Drug: belinostat
Other: laboratory biomarker analysis

Registration Number: NCT00365053

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (belinostat)	laboratory biomarker analysis	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.
Treatment (belinostat)	belinostat	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.

Primary Outcome Measures

Name	Time	Method
Objective Tumor Response Rate According to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee	Up to 3 years	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

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Up to 3 years	Estimated using the product-limit method of Kaplan and Meier.
Progression-free Survival	Up to 3 years	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.
Apoptosis by TUNEL Assay	At baseline	Summarized with contingency tables or scatterplots, and with quantitative measures of agreement.
Toxicity Profile	Up to 3 years	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.
Histone Acetylation by IHC and Western Blotting	At baseline and at 4 hours after last dose of PXD101 on day 5	Summarized with contingency tables or scatterplots, and with quantitative measures of agreement.