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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Malignant Mesothelioma; Advanced Malignant Mesothelioma; Epithelial Mesothelioma; Sarcomatous Mesothelioma
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: belinostat

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment (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.	Other: laboratory biomarker analysis; Correlative studies; Drug: belinostat; Given IV; Other Names: PXD101

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Suresh Ramalingam, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (ACTUAL): March 1, 2009
• Study Completion (ACTUAL): March 1, 2009

Study Registration Dates

• First Submitted: August 16, 2006
• First Submitted That Met QC Criteria: August 16, 2006
• First Posted (ESTIMATE): August 17, 2006

Study Record Updates

• Last Update Posted (ACTUAL): June 7, 2018
• Last Update Submitted That Met QC Criteria: May 4, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Belinostat
• Other Study ID Numbers: NCI-2012-02839; N01CM62209 (U.S. NIH Grant/Contract); PHII 67